Abstract
Most commonly recognized as a catabolic pathway, autophagy is a perplexing mechanism through which a living cell can free itself of excess cytoplasmic components, i.e., organelles, by means of certain membranous vesicles or lysosomes filled with degrading enzymes. Upon exposure to external insult or internal stimuli, the cell might opt to activate such a pathway, through which it can gain control over the maintenance of intracellular components and thus sustain homeostasis by intercepting the formation of unnecessary structures or eliminating the already present dysfunctional or inutile organelles. Despite such appropriateness, autophagy might also be considered a frailty for the cell, as it has been said to have a rather complicated role in tumorigenesis. A merit in the early stages of tumor formation, autophagy appears to be salutary because of its tumor-suppressing effects. In fact, several investigations on tumorigenesis have reported diminished levels of autophagic activity in tumor cells, which might result in transition to malignancy. On the contrary, autophagy has been suggested to be a seemingly favorable mechanism to progressed malignancies, as it contributes to survival of such cells. Based on the recent literature, this mechanism might also be activated upon the entry of engineered nanomaterials inside a cell, supposedly protecting the host from foreign materials. Accordingly, there is a good chance that therapeutic interventions for modulating autophagy in malignant cells using nanoparticles may sensitize cancerous cells to certain treatment modalities, e.g., radiotherapy. In this review, we will discuss the signaling pathways involved in autophagy and the significance of the mechanism itself in apoptosis and tumorigenesis while shedding light on possible alterations in autophagy through engineered nanomaterials and their potential therapeutic applications in cancer.
SIGNIFICANCE STATEMENT Autophagy has been said to have a complicated role in tumorigenesis. In the early stages of tumor formation, autophagy appears to be salutary because of its tumor-suppressing effects. On the contrary, autophagy has been suggested to be a favorable mechanism to progressed malignancies. This mechanism might be affected upon the entry of nanomaterials inside a cell. Accordingly, therapeutic interventions for modulating autophagy using nanoparticles may sensitize cancerous cells to certain therapies.
Introduction
Several types of cell death determine the ultimate fate of a living organism. This phenomenon is an integral part of life, as it maintains homeostasis by exterminating redundant cells that may otherwise become a liability. Through the never-ending course of evolution, various mechanisms of cell death have emerged, including apoptosis, necroptosis, and autophagy-dependent cell death (Kang et al., 2011; Su et al., 2015).
A self-digestive process, type II or autophagic cell death (Gozuacik and Kimchi, 2004) is one such mechanism that regulates lysosomal degradation of superfluous or erroneous materials, e.g., damaged organelles and misfolded proteins (Choi, 2012). Accordingly, autophagy is a regulatory process in which cytoplasmic vesicles with multiple membranes appear inside a cell and start engulfing bulks of cytoplasmic organelles only to disintegrate them from the cell. These so-called autophagic bodies are subsequently degraded by the lysosomal system of the very same cell. It is believed that autophagy is fundamentally different from the ordinary turnover cycle of organelles, as it assumes a broader scope in maintenance of cellular activity in conditions that, if not counteracted, might render the organism susceptible. During this process, the cell simply cannibalizes itself from the inside (Gozuacik and Kimchi, 2004). On a basal level, autophagy contributes to maintaining homeostasis by mediating the turnover of proteins and organelles; however, it can be accelerated in response to stress as a survival mechanism (Choi 2012). Based on the molecular pathways associated with the biogenesis of autophagic vesicles or autophagosomes, autophagy can be classified as canonical or noncanonical. In this regard, autophagy-related or ATG genes are also categorized into two eponymous classes, of which more than 30 members have been discovered (Rebecca and Amaravadi, 2016).
Once presumed to be a survival mechanism in yeasts under starvation, autophagy has now been recognized as a universal process involved in many cell types, particularly mammalian, that plays a major part in cellular function (Zhang et al., 2009). In fact, the phenomenon is so crucial that, if defected, certain ailments may arise as a consequence, e.g., infection, aging, neurodegeneration, myopathy, Crohn disease, and malignancies (Levine and Kroemer, 2008). In spite of all the controversies around the footprint of autophagy in malignancy, it appears that the mechanism assumes an ambivalent approach in development of tumors, as despite being a tumor-suppressive process, autophagy might contribute to the survival of malignant cells (Rosenfeldt and Ryan, 2009). Besides, tumor cells can exploit autophagy to gain resistance against several antitumor agents (Chen and Karantza-Wadsworth, 2009). Because of their rapid proliferation and altered metabolism, cancer cells are subject to more stress and have higher metabolic demands (White and DiPaola, 2009), which might render them more dependent on autophagy as a survival mechanism (Amaravadi et al., 2011).
Recently, several studies have reported certain correlations between autophagy and nanotechnological interventions. Pieces of evidence have recently suggested the significance of autophagy in development of adaptive reactions to nanomaterials. However, the nature of such reactions is yet to be elucidated, as they often happen to vary with physicochemical properties of nanomaterials that become taken up by the cells to which they are introduced. In this regard, it can be asserted that autophagy grants the cell with cytoprotective effects in response to the uptake of foreign materials, which in this case are nanomaterials (Popp and Segatori, 2015).
Nanoparticles (NPs) are now recognized as novel materials with a capacity to induce autophagy (Zhang et al., 2009). Different NPs, such as quantum dots (QDs), nanowires, and the more recently studied rare earth oxides, can reportedly induce autophagy in cells derived from different tissues, e.g., mesenchymal stem cells, cervical cancer cells, etc. (Stern et al., 2008; Zhang et al., 2010b). QDs were first documented to exert size-dependent autophagy-inducing effects on human mesenchymal stem cells in 1999 (Seleverstov et al., 2006). It was only a decade later that an investigation on QDs with different core materials revealed that these particles were able to induce autophagy in porcine kidney cells, further supporting the theory that autophagy might be a common cellular response to nanomaterials. Interestingly, the effects of cellular stress on autophagy are determined by cell type and the kind of stimuli (Stern et al., 2008). Another study in 2011 implicated that iron oxide NPs could be used for treatment of tumors, as they had the potential to mediate autophagy in malignant cells (Khan et al., 2012).
A well founded understanding of mechanisms involved in the regulation of autophagy in malignancy and their response to nanomaterials might open a new pathway toward developing novel therapeutic interventions that can modulate this pathway either directly or indirectly. The present article will discuss the most recent advancements in understanding of autophagy in malignancy and the potential regulatory role of NPs in it.
Autophagy: Involved Pathways
Autophagy, also known as type II cell death (Gozuacik and Kimchi, 2004), is a conserved catabolic process that can be considered as one of the main degradative pathways of unnecessary or dysfunctional cellular components, old or misfolded proteins, and superfluous or defected organelles in eukaryotic organisms (Kondo and Kondo, 2006). Besides, autophagy has a crucial role in eliminating pathogens and engulfing apoptotic cells (Mathew et al., 2007). Microautophagy, macroautophagy, and chaperone-mediated autophagy are three known types of autophagy, of which macroautophagy is the primary type that occurs most frequently in eukaryotic cells (Li et al., 2017). In Saccharomyces cerevisiae, overlapping Atg genes, including Apg, Aut, and Cvt, have been found to be involved in the autophagic pathway (Gozuacik and Kimchi, 2004). Factors such as nutrient deprivation, reactive oxygen species (ROS), hypoxia, drug stimuli, aggregated proteins, and damaged organelles mainly induce autophagy, causing cells to degrade macromolecules, including proteins, lipids, and carbohydrates, to synthesize essential cell components (Choi et al., 2013; Mei et al., 2014).
Basal autophagy brings about protein degradation and organelle turnover and is a vital factor in intracellular quality control and sustaining homeostasis. At the same time, it has been revealed that autophagy is also triggered in stressful conditions to maintain cell survival (Choi, 2012). Upon receiving the signal from the cell, a cascade of reactions occur that result in the surrounding of cytoplasmic constituents by intracellular double-membraned structures to form the autophagosomes (Levine, 2007; Zhang et al., 2009).
At first, cytoplasmic constituents are enwrapped by a membrane sac to form vesicles (Gozuacik and Kimchi, 2004). These vesicles subsequently fuse with lysosomes. After the release of lysosomal digestive enzymes into the lumen of the resulting autolysosomes, the internal contents are digested by lysosomal hydrolases. The degradation products are then recycled back to the cytosol and reused by the cell to maintain energetic homeostasis and viability (Levine, 2007; Zhang et al., 2009).
In normal cells and tissues, autophagy plays a complex and tissue-dependent role (Mizushima and Komatsu, 2011). As a cellular housekeeper, autophagy maintains homeostasis by eliminating inessential proteins and nonfunctional organelles in normal physiologic conditions (Mathew et al., 2009; Anding and Baehrecke, 2017). In this regard, aberrant regulation of autophagy can lead to severe conditions, including neurologic disease, infection, myopathy, inflammation, aging, and a variety of cancers (Choi, 2012; Yin et al., 2016). To our knowledge, the process of autophagy depends on the continuous presence of ATP along with uninterrupted protein synthesis (Gozuacik and Kimchi, 2004). Figure 1 represents involved signaling pathways.
Mechanisms involved in autophagy. Stressors such as starvation and infection can induce autophagy. Upon nutrient deficiency in the environment, autophagy is usually triggered in S. cerevisiae to provide the prerequisite amino acids and macromolecules for the survival of the microorganism. A nutrient sensor, TOR protein kinase, is the primary molecule responsible for the regulation of autophagy inside the cell, which has been mostly investigated in fungal cells, particularly yeasts (Gozuacik and Kimchi, 2004). When nutrients are amply available, TOR protein kinase prompts phosphorylation of Apg13, the affinity of which for Apg1 significantly decreases upon hyperphosphorylation, resulting in reduced Apg1 kinase activity (Kamada et al., 2000; Scott et al., 2000) and concomitant activation of the Cvt pathway. Administration of rapamycin or inaccessibility to nutrients, in contrast, leads to inhibition of TOR protein kinase and subsequent dephosphorylation of Apg13. The resulting increase in the activity of Apg1 thus prompts autophagy (Gozuacik and Kimchi, 2004). In this circumstance, autophagy is mediated through macroautophagy and mitophagy (Popp and Segatori, 2015). In the former, the PI3K/Akt and MAPK/ERK1/2 pathways become initiated and are then succeeded by inhibition of mTOR and activation of beclin 1/Atg6. Mitophagy, however, is triggered after mitochondrial damage and the activity of ubiquitin-like conjugation systems. Further down the cascade, an interaction between p62 and LC3-II results in cargo delivery to autophagic membranes or phagophores. Fusion of the phagophores surrounding the cargo material results in formation of autophagosomes, structures that subsequently bud into lysosomes to form autophagolysosomes or degradation center. ROS can induce autophagy through several different mechanisms: nuclear PTEN, the PI3K pathway, and LKB1/AMPK. Rapamycin acts as an mTOR inhibitor (Popp and Segatori, 2015; Díaz-Troya et al., 2008). Rubicon, 3-MA, and chloroquine function to inhibit autophagy (Zhang et al., 2014b; Rebecca and Amaravadi 2016). Activation of p53 leads to upregulation of DRAM and sestrin 1/2, which ultimately accelerates autophagy. p70S6K might be a good option for controlling autophagy downstream to mTOR (Gozuacik and Kimchi, 2004). ALFY, autophagy-linked FYVE protein; Ambra, activating molecule in beclin 1–regulated autophagy; AMPK, AMP-activated protein kinase; BNIP3, BCL2 and adenovirus E1B 19 kDa-interacting protein 3; BNIP3L/NIX, BNIP3-like; ERK, extracellular signal-regulated kinase; FIP200, focal adhesion kinase family interacting protein of 200 kDa; GBL, γ-butyrolactone; HMGB1, high mobility group box protein 1; LIR, LC3-interacting region; LKB1, liver kinase B1; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; NBR1, neighbor of BRCA1; PE, Phosphatidylethanolamine; P150, a mammalian homolog of yeast Vps15; P53, tumor protein p53; PARL, presenilin-associated rhomboid-like protein; PRAS40, proline-rich Akt substrate of 40 kDa; p70S6K, ribosomal protein S6 kinase β-1; PTEN, phosphatase and tensin homolog; Raf, rapidly accelerated fibrosarcoma; RAPTOR, regulatory-associated protein of mTOR; Ras, rat sarcoma; SQSTM1/P62, sequestosome-1; ub, ubiquitin; ULK1, Unc-51-like kinase 1.
Phosphatidylinositol 3-Kinase Complex
Phosphatidylinositol 3-kinase (PI3K) pathway is primarily involved in the autophagy process (Petiot et al., 2000). The pathway is of crucial importance for endocytic and phagocytic trafficking and formation of autophagic vesicles (Mizushima et al., 2001; Simonsen and Tooze, 2009; Burman and Ktistakis, 2010). According to several studies, 3-methyladenine (3-MA), an autophagy inhibitor, and Wortmannin, a phosphatidylinositol 3-kinase inhibitor, can inhibit the generation of autophagosome precursors in mouse embryonic stem cells (Mizushima et al., 2001).
Tor Kinase and Apg Expression
Considered a gatekeeper against the triggering factors of autophagy (Liang, 2010), Tor kinase plays a role in Akt signaling pathway by relaying growth factor–induced signals to the main pathway of autophagy. Accordingly, Tor kinase inhibitors, e.g., rapamycin, can induce autophagy in both yeast and mammalian cells (Díaz-Troya et al., 2008). Inhibition of Tor kinase pathway is thought to increase Apg8 expression (Kirisako et al., 1999), which is an important gene in formation and expansion of autophagic vesicles (Gozuacik and Kimchi, 2004). Phosphorylation of certain proteins in this pathway coincides with suppression of autophagy in mammalian cells (Blommaart et al., 1997).
Ubiquitin-Like Systems
Formation of autophagic vesicles relies on two major ubiquitin-like conjugation systems. In the more predominant systems, an E1-like enzyme called Apg7 is conjugated with Apg12 and then translocated to an E2-like enzyme, Apg10 (Shintani et al., 1999). Next, a covalent linkage is formed between the C terminus of Apg12 and the central part of the Apg5 protein (Mizushima et al., 1998). Nearly all Apg12 molecules in cells are conjugated with Apg5. In this case, Apg12/Apg5 conjugation is not affected by stimuli that may otherwise induce autophagy (Gozuacik and Kimchi, 2004).
Apoptosis
Type I cell death or apoptosis is a cellular process characterized by the fragmentation of the cell into smaller membraned structures called an apoptotic body, which usually succeed alterations in the nucleic material—namely, condensation of chromatin and degradation of the DNA. The remaining components of the cell are then digested by phagocytes after heterophagocytosis (Gozuacik and Kimchi, 2004).
Apoptosis is usually mediated via two different cascades, the extrinsic and intrinsic pathways, that result in degradation of cellular organelles (Nagata, 2018). The extrinsic apoptotic pathway involves membranous death receptors like CD95 (FAS), TRAIL receptors, and tumor necrosis factor (TNF) receptor family, which bind to specific ligands such as soluble TNF. Upstream to these receptors, there are several caspases that function to mediate the process. Caspase-8 and caspase-10 activate the effector caspases, known as caspase-3, -6, and -7, resulting in final-stage molecular degradation involved in apoptosis (Andreeff, 2003). Mitochondria are the central part of the intrinsic pathway of apoptosis. Proapoptotic molecules such as Bcl2-associated death, Bax, Bak, Noxa, Bid, and p53 upregulated modulator of apoptosis constitute the intrinsic apoptotic pathways. In this case, Bak and Bax can dimerize and, therefore, permeabilize the outer membrane of mitochondria. As a result, cytochrome C is released into the cytosol and interacts with apoptotic protein activating factor-1, leading to the assembly of apoptosome. This multiprotein structure can activate caspase-9 and other effector caspases (Kang and Reynolds, 2009).
Autophagy and Apoptosis: Possible Links and Differences
The link between autophagy, apoptosis, and other types of cell death is an area of interest to researchers (Kang et al., 2011), especially in cancer research. Apoptosis is one type of programmed cell death that can be triggered by intra- or extracellular stimuli through activation of a cascade of proteases (Nagata, 2018). On the other hand, autophagy or cellular “self-eating” is a mechanism in which a section of the cell is surrounded by a special intracellular membrane, and its contents are then digested by lysosomal enzymes (Hurley and Young, 2017). Autophagy is like a double-edged sword since it is often induced as a response to stress to prevent cell death through aplysia ras homolog I (ARHI)-dependent pathway. Nonetheless, in some special occasions, it can serve as a means of cell death (Fulda et al., 2010).
There are contradictive data on the interaction between autophagy and apoptosis. Several stressors can trigger autophagy, e.g., apoptosis-inducing chemotherapeutic agents (Verfaillie et al., 2010), dysfunction of cellular organelles (Anding and Baehrecke, 2017), starvation (Li et al., 2013b), etc. Exposure to such stressors might activate autophagy, which can restore the cell to its normal status. But, in the long-term, the cell may undergo apoptosis. It can be concluded that unlike apoptosis, autophagy is a pathway toward survival of the cell; however, should there be prolonged exposure to stress, the cell may die by means of autophagic cell death (Shen et al., 2012). Figure 2 represents the link between autophagy and apoptosis.
Correlation of apoptosis and autophagy. Oxidative stress, pathogens, and cell death signals can induce autophagy or apoptosis through either dependent or independent pathways. [Modified from Gozuacik and Kimchi (2004).]
Implications in Cancer
Not only are autophagy and apoptosis independent, but they also have multiplex crosstalk with each other in physiologic and pathologic incidents like cancer. The tumor-suppressing function of apoptosis is supported by the recent evidence (Chao et al., 2006); however, autophagy is a rather different mechanism that serves as an intricate function in the onset and development of tumors (Sun et al., 2013). Unlike apoptosis, the function of autophagy in tumor cells is partly favorable and partly unfavorable; hence, it can both instigate and halt tumor development (Eskelinen, 2011). It has been argued that cancer cells benefit from autophagy, as it enables them to survive the exposure to several tumor microenvironment stressors such as hypoxia, starvation, and metabolic stresses (Dikic et al., 2010). Besides cancer, other diseases can also occur with this mechanism because of the abnormal balance between autophagy and apoptosis or linkage gene concept. For instance, Atg5 deficiency can induce apoptosis as a result of stress to endoplasmic reticulum and lead to cardiovascular diseases (Nishida et al., 2008).
Can Autophagy Hinder or Aggravate Cancer?
Defects in autophagy contribute to the etiology of many diseases, such as cancer (Kondo and Kondo, 2006). Most studies have indicated the ambivalent nature of autophagy in cancer (Fiaschi and Chiarugi, 2012). Likewise, a remarkable body of published studies have pointed to the function of autophagy in tumor suppression (Mei et al., 2014). Accumulating evidence indicates that there might be a link between cancer and autophagy at two levels of cancer progression and cancer prevention. For example, inactivation of some autophagy genes has been shown to lead to increased tumorigenesis in mice (Ni et al., 2014). On the other hand, enforced expression of certain autophagy genes was reported to prevent formation of tumors (Levine, 2007). It has also been noted that autophagy can be activated in response to chemotherapeutic drugs in cancer cells (Karantza-Wadsworth and White, 2007). Figure 3 and Table 1 represent the correlation between autophagy and tumorigenesis.
Autophagy in tumor cells. Oncogene products (blue) inhibit autophagy, whereas tumor suppressors (green) accelerate autophagy, except for cytoplasmic p53. Growth factor signaling through activation of the PI3K/Akt/mTOR axis leads to inhibition of autophagy. On the contrary, class III PI3K activates autophagy. Low levels of cellular energy with an increased AMP/ATP ratio activate the LKB1-AMPK-mTOR pathway, which ultimately results in upregulation of autophagy. p53 is a complex regulatory factor in the process of autophagy, as nuclear p53 activated by genotoxic or oncogenic stress positively regulates autophagy by inhibiting mTOR in an activated AMPK- and TSC1/TSC2-dependent manner. In contrast, cytoplasmic p53 has a negative regulatory effect on autophagy. Autophagy can also be induced by the cell death–associated protein kinase (DAPK) and the death-associated related protein kinase 1 (DRP1). AMPK, AMP-activated protein kinase; Bad, Bcl2-associated death; Bnip3, BCL2 and adenovirus E1B 19 kDa-interacting protein 3; ERK, extracellular signal–regulated kinase; Foxo3A, forkhead box class O 3a; IRS, insulin receptor substrate; LKB1, liver kinase B1; MEK, MAPK kinase; mLST8, mammalian lethal with Sec13 protein 8; P16, CDKN2A; P21, cyclin-dependent kinase inhibitor 1A; P27, cyclin-dependent kinase inhibitor 1B; P53, tumor protein p53; PRAS40, proline-rich Akt substrate of 40 kDa; PTEN, phosphatase and tensin homolog; Puma, p53 upregulated modulator of apoptosis; Raf1, rapidly accelerated fibrosarcoma; Raptor, regulatory-associated protein of mTOR; Ras, rat sarcoma; RB, retinoblastoma; Rheb, Ras homolog enriched in brain; Sestrin, cysteine sulfinic acid reductase; TAK1, TGF-β–activated protein kinase 1; TSC, tuberous sclerosis protein. [Modified from Choi (2012).]
Correlation between autophagy and tumorigenesis
A series of in vitro experiments showed that enhanced activity of beclin 1, an autophagy-inducing protein, might reduce the proliferation of cancer cells (Liang et al., 1999). It was also revealed that downregulation of beclin 1 might promote the tumorigenicity of Hela cells (Wang et al., 2007b). In another study, scientists were able to show that beclin 1 overexpression by RNA interference methods reduced the proliferation and migration of cancer cells, introducing this protein as a potential target for cancer treatment modalities (Sun et al., 2011b). In 2011, scientists reported that induced autophagy by means of docosahexaenoic acid could augment the apoptosis rate by affecting caspase-3 function in cancer cells (Jing et al., 2011). It was only 2 years later that another investigation confirmed the desirable effects of kaempferol in treatment of cancer cells, which included arrestment of cell cycle and induction of autophagic cell death (Huang et al., 2013). Several years later, it was reported that a treatment regimen comprising beclin 1–derived protein hindered the proliferation of HER2-positive breast cancer cells (Vega-Rubín-de-Celis et al., 2018). It was also shown that most important autophagy-related genes, like beclin1, atg5, bif-1, and atg4c, had been lost in the genome of prostate, ovarian, and breast cancer cells (Maes et al., 2013). Allegedly, a combined therapy of autophagy targeting and radiotherapy might prove to be more effective than radiotherapy alone. Accordingly, downregulation of beclin-1, atg3, atg4b, atg4c, atg5, and atg12 could sensitize cancer cells to radiation (Apel et al., 2008). Recently, cisplatin-induced autophagy in ovarian cancer was inhibited by bortezomib, a proteasome inhibitor, to increase the efficacy of chemotherapy (Kao et al., 2014). Bufalin, in a similar way, causes autophagy-mediated cell death through ROS production and enhanced radiosensitivity in human colon cancer cells (Xie et al., 2011).
Thus, it can clearly be inferred that autophagy should not be considered a definitive solution, but rather, it should be regarded as a doubtful advantage with two sides, each of which have been well supported by several investigations. (Jiang et al., 2019). Through the removal of damaged DNA and organelles in the preliminary stages of tumorigenesis, autophagy acts as a protective mechanism to maintain the integrity of the cell and prevent instigation of malignancy (Hönscheid et al., 2014). A pivotal mechanism for migration and invasion of tumor cells, epithelial-to-mesenchymal transition (EMT) can be counteracted by induction of autophagy, thus hindering tumorigenesis (Lv et al., 2012; Catalano et al., 2015). However, as the tumors progress in stage, autophagy assumes a seemingly paradoxical role by delivering essential nutrients to the tumor cells through degradation of unnecessary intracellular structures, resulting in the emergence of resistant tumor cells (Cheong, 2015). Therefore, development of an effective autophagy-based cancer therapy for the treatment of malignancies is a rather complicated task for clinicians (Jiang et al., 2019).
For centrally located tumor cells, autophagy can be an excellent option for cancer cells to survive and continue tumorigenesis. In this case, autophagy may function as a big barrier against most routine cancer therapies (Kimmelman, 2011). Unlike the aforementioned data, dozens of studies have revealed that autophagy is another side of the sword that can help with the maintenance of tumor cells (Gong et al., 2013; Guo et al., 2016), as it contributes to their escape from the immune system (Noman et al., 2011). Table 2 summarizes the autophagic genes involved in cell death, invasion, and tumor dormancy (Liang et al., 2006; Wang et al., 2007a; Criollo et al., 2009; Kang et al., 2009; Mathew et al., 2009; Dimco et al., 2010; King et al., 2011; Capparelli et al., 2012; Gundara et al., 2012; Schmitt et al., 2012; Wu et al., 2012, 2013; Kenzelmann Broz et al., 2013; Lindqvist and Vaux, 2014; Maes et al., 2014; Murthy et al., 2014; Fernández and López-Otín, 2015; Poillet-Perez et al., 2015; Richmond et al., 2015; Su et al., 2015; Washington et al., 2015; Xie et al., 2015; Attar-Schneider et al., 2016; Cubillos-Ruiz et al., 2017; El Andaloussi et al., 2017; Galluzzi et al., 2017; Karch et al., 2017; Aqbi et al., 2018a; Chen et al., 2018a; Cusan et al., 2018; Liu et al., 2018b,c; Maruyama and Noda, 2017; Tong et al., 2018; Vera-Ramirez et al., 2018; La Belle Flynn et al., 2019; Li et al., 2020).
The autophagic genes involved in cell death, invasion, and tumor dormancy
Nanotechnology
A large number of studies have been conducted on wide-ranged applications of nanomaterials (NMs) only to discover their peculiarly unfavorable effects. In terms of cell function and molecular pathway, NMs often cause profound adverse biologic effects (Setyawati et al., 2013a; Tay et al., 2013; Afzalipour et al., 2019; Shirvalilou et al., 2020). Nanotechnology has multiple applications with a scientific impact; however, the underlying pathways in interaction of NMs with biologic systems at a molecular level still remain to be elucidated. These controversies raise concerns for utilizing nanoscale particles in targeted cancer therapies (Warheit, 2010; Setyawati et al., 2013b; Changizi et al., 2020b).
The Link between Autophagy and Nanotechnology
NPs have been widely used as beneficial research tools for modulating the process of autophagy. Autophagy abnormalities are associated with several disorders, including cancer and cardiovascular, metabolic, and neurodegenerative diseases (Ghavami et al., 2014). Hence, NP-related autophagy modulations are suggested to be a state-of-the-art therapeutic intervention for treatment of such conditions. Induction of oxidative stress–dependent signaling (ER stress, mitochondrial damage, etc.), inhibition of Akt-mTOR signaling, and alteration of the expression of autophagy-related gene/protein stand among the primary mechanisms by which NMs modulate autophagic pathway (Wu et al., 2014). Figure 4 and Table 3 represent the link between autophagy and nanotechnology in cancer.
Mechanisms involved in nanomaterial-regulated activation of autophagy. Nanomaterials may induce autophagy through different mechanisms, including enhanced formation of autophagosomes, induction of oxidative stress, and instigation of lysosomal damage. Based on the nature of the nanomaterial, activation of autophagy might result in enhanced clearance or blockage of autophagic flux. Upon their release into the cytoplasm, nanomaterials may also impair the cytoskeleton integrity and function, leading to autophagosome dysfunction and blockage of autophagic flux. Else, nanomaterials can also enhance the formation and functioning of lysosomes, and autophagosomes and induce autophagy. AMPK, AMP-activated Protein Kinase; Cas, caspase; ERK, extracellular signal–regulated kinase; HO-1, heme oxygenase-1; MEK, MAPK kinase; MMP9, matrix metallopeptidase 9; NF-kB, nuclear factor κ-light-chain-enhancer of activated B cells; P38, mitogen-activated protein; P53: tumor protein p53; P62, sequestosome 1; Raf, rapidly accelerated fibrosarcoma; Ras, rat sarcoma; TLR, Toll-like receptor; TRIF, TIR-domain–containing adapter-inducing interferon-β; VEGF, vascular endothelial growth factor.
Interaction between nanotechnology and autophagy in cancer
Can NMs Turn On or Turn Off Autophagy? Which One Is Preferable for Killing Tumor Cells?
The paradoxical nature of autophagy can be turned into an advantage for development of cancer treatment modalities, as the mechanism is thought to be a driving factor of early survival and late cell death in tumor progression and cancer therapy (Singh et al., 2018). Thus, the role of NMs in cancer therapy enhancement is incontrovertible (Beik et al., 2017; Ghaznavi et al., 2018; Abed et al., 2019; Beik et al., 2019; Mirrahimi et al., 2019). In the last decade, inhibition of autophagy was introduced as a strategic mechanism in cancer therapy. A growing number of studies are being dedicated to delineating the link between NMs and autophagy to see whether NMs are exploitable tools in cancer therapies (Wei and Le, 2019). Since then, an expanding number of NMs ranging from soft NMs, liposomes, and polymeric NPs to hard NMs such as cerium dioxide NPs, zinc oxide, iron oxide (IONPs), silver, gold, and titanium dioxide NPs, QDs, carbon nanotubes (CNTs), graphene oxide, silica NPs, and fullerenes have been shown to possess remarkable properties for modulating autophagy (Hussain et al., 2012; Yu et al., 2014b; Zheng et al., 2016). Chemical composition, morphology, and surface chemistry, as well as the size of NMs, determine whether a NP is likely to trigger autophagy under certain conditions. In other words, NPs can be considered as both inducer and inhibitor of autophagy in the target cell based on their size and morphology (Popp and Segatori, 2015; Zhang et al., 2018).
Nevertheless, NP-mediated autophagy is associated with nanotoxicity (Sarkar et al., 2014). To boost the therapeutic efficacy and develop safer NMs, scientists investigated the variations of CNTs’ surface ligand and their impact in modulating the extent to which autophagy is triggered. They reported that the surface modification of CNTs might result in potential pharmaceutical autophagy modulators and biocompatible NMs (Wu et al., 2014).
Turn-On Effects of NMs
Positive turn-on effects: prodeath nature of autophagy.
Various NMs, including metallic-based NPs (Cordani and Somoza, 2019) and light and heavy nanocrystals (Yu et al., 2009), can trigger autophagy. In 2005, scientists showed that nanosized neodymium oxide induced extensive autophagy in NCI-H460 human lung cancer cells (Chen et al., 2005). After that, NM-related autophagy was generally believed to be a prodeath mechanism. The only way to acquire knowledge on the likelihood of such claims was to evaluate cell death while inhibiting autophagy. For clarification, it was shown that both molecule inhibitors and Atg5 gene knockdown dramatically reduced the rate of death in HeLa cells incubated with ZnO NPs, indicating that these NMs triggered prodeath autophagy (Hu et al., 2019). This was suggested to be a positive effect of NMs in cancer therapy through the regulation of oxidative stress and autophagy, which led to cell death. In this case, NMs served as cytotoxics and/or enhanced the efficiency of typical chemotherapies (Sun et al., 2014).
To enhance the efficiency of epidermal growth factor receptor (EGFR)-oriented triple-negative breast cancer therapy, scientists developed EGFR-targeted gold NPs to induce autophagy. In this case, autophagy induction rendered the cancer cells more susceptible to photothermal therapy (PTT) (Zhang et al., 2017b). They discovered that poly(lactic-coglycolic acid) (PLGA)-based NPs were able to trigger autophagy in tumor cells. In this modality, NPs were swallowed by autophagosomes before being delivered to degradative organelles (Zhang et al., 2014b). Modified PLGA-based NPs significantly enhanced the activity of autophagosomes compared with nonmodified counterparts. In this study, induction of autophagy via docetaxel-containing NPs contributed to impaired intratumoral drug delivery (Liu et al., 2011).
In another study, redox-responsive nanohybrid GCMSNs were synthesized through gold nanoparticle attachment onto amine-functionalized MSNs. Compared with normal 3T3-L1 cells, GCMSNs induced higher oxidative stress–triggered autophagy in A549 lung cancer cells. Synergism, through the combination of chemotherapy and oxidative stress–induced autophagy via camptothecin-loaded nanohybrids, resulted in a superior nanocarrier system for highly effective cancer therapy (Lu et al., 2015). Despite that, autophagy-mediated cell death is still somehow challenging if the normal cells become involved as well. To address this issue, one should ascertain the selectivity of NP-based autophagy, as it must only be triggered in cancer cells.
The best targets for autophagy-mediated therapy are autophagy-deficient cancer cells. Lack of beclin 1 protein required for initiation of autophagosome formation in autophagy is a determining factor. Therefore, designing autophagy-inducing peptides engineered into polymeric NPs (Bec1) could significantly enhance autophagy-mediated cell death in these cells (Wang et al., 2015a).
NP-induced autophagy sometimes appears to be useful for cancer therapy, especially against drug-resistant variants, if it were coupled with autophagy-mediated chemosensitization. Fullerene c60, which induces autophagy in tumor cells, was reported to enhance the chemosensitization of both normal and drug-resistant cancer cells. Thus, the subsequent reduction in drug resistance may eventually establish novel therapeutic strategies for cancer treatment (Wei et al., 2010).
Negative turn-on effect: prosurvival nature of autophagy.
To form a verdict on nanorelated autophagy-inducing effect in cancer therapy from another perspective, it is appropriate to note the ineffectiveness of Chemo-PTT combination therapy approach in drug-resistant cancer. Turning on the prosurvival autophagy is thought to be a great solution to this issue. With a high absorption in the near-infrared region, NMs can also induce prosurvival autophagy. The recent application of custom-designed copper (Cu)-palladium (Pd) alloy tetrapod NPs in Chemo-PTT is considered a novel approach that combines chemotherapy and PPT. Thanks to their unique structure, these NPs elicited an ideal photothermal conversion potential and induced prosurvival autophagic cell death. This achievement paved the way for application of custom-designed NPs as autophagy-suppressing agents rather than the conventional therapeutic agents (Zhang et al., 2018). In contrast to the most noted autophagy-related cell death by NMs, nanosized paramontroseite VO2 nanocrystals were reported to induce cytoprotective autophagy in cultured HeLa cells (Zhou et al., 2013). Furthermore, several NMs were also reported to induce prosurvival autophagy (Zhang et al., 2019).
This increased level of protective autophagy (prosurvival autophagy) could hamper anticancer therapies. In such cases, autophagy might function as a cellular protector against NP-induced cytotoxicity in various tumor cell lines. Therefore, autophagy inhibitors have been widely used in company with drug-delivery NMs to improve the treatment efficiency. Hence, when deciding to modulate autophagy for enhancing treatment efficiency, one should consider whether the combined regimen enhances or dampens autophagic activity in tumor cells to accurately determine the modulation method (Høyer-Hansen and Jäättelä, 2008; Das et al., 2019).
Turn-Off Effects of NMs
In addition to the above mechanisms, a number of studies suggest that NMs are capable of perturbing autophagic pathways by inhibiting Akt-mTOR signaling or altering the expression of autophagy-associated genes/proteins (Li et al., 2009; Zhang et al., 2009; Liu et al., 2011). Therefore, compared with the well studied NMs that induce autophagy, inhibitory types are still rare. Citric acid–capped gold, REO, and IONPs have been known as blockers of autophagic activity; however, their mechanism of action and cellular targets are still ill-defined. In a recent study, custom-designed titania‐coated gold nano‐bipyramids functioned as an innovative autophagy inhibitor for sensitizing U-87 MG brain tumor cells to proteasome inhibitor–induced cell death. Moreover, nanodiamonds (NDs) were recently shown to inhibit autophagy in oxygen-deprived tumors in a synergistic manner (Wan et al., 2017). In practical terms, high levels of autophagy under hypoxia is an adaptive strategy adopted by cancer cell for survival. Therefore, ND-related autophagy inhibition, along with oxygen deprivation, may cause significant apoptosis in HeLa cells and MCF-7 cells (Chen et al., 2018b). In a similar study led by Sun et al. (2016), inhibition of autophagy resulted in sensitization of MDA-MB-231 cells to conventional chemotherapeutics.
NMs have the potential to either induce or inhibit the autophagic pathways. Still, more research on this topic needs to be conducted to delineate the link between NMs and autophagy.
Effects of NMs on Tumor Dormancy: Focusing on Involved Signaling Pathways
NPs can influence the autophagic pathway in different ways; however, their role in the induction of tumor dormancy may hinder their practical applications. Autophagy plays a crucial role in preserving tumor cells in a prolonged state of arrest and senescence that can be followed by apoptotic cell death (Polewska et al., 2013). That is to say, autophagy may be directly associated with tumor dormancy, as the senescent cells might recover their proliferative capability, giving rise to renewed tumor growth and metastasis (Gewirtz 2009). Nonetheless, PTT therapy has limited capacity for total eradication of tumor cells, as adjacent cells could be very well damaged by mild hyperthermia. In this case, heat shock proteins would naturally be recruited to repair the damaged cells, resulting in tumor relapse and, eventually, escape of tumor from dormancy (You et al., 2019).
Dormant tumor cells often gain drug resistance that protects them against chemotherapy (Aguirre-Ghiso, 2007). In 2006, scientists established a link between the activation of the p38 signaling pathway and induction of tumor dormancy. They demonstrated how enhanced activation of PERK, an RNA-dependent protein kinase, compels dormant squamous carcinoma cells to develop drug resistance (Ranganathan et al., 2006). Several newly designed NMs were reported to activate p38 signaling and, therefore, induce drug resistance (Eom and Choi, 2010; Skuland et al., 2014). These NMs are conjugated to drugs and circumvent poor drug retention into the tumor cells for efficient targeting. However, either the induction or inhibition of autophagy could have profound impacts on drug resistance reversal (Panzarini and Dini, 2014). One particular investigation in 2018 adopted hyaluronic acid–based nanoparticles for targeting tumor stem cells to decrease their drug resistance as a result of dormancy. In this work, the previously known antitumor agents (e.g., camptothecin, doxorubicin hydrochloride, or curcumin) were codelivered to malignant stem cells via four multilayered core-shell polymeric nanoparticles that were synthesized from different chitosan-modified polymers (Wang and He, 2018).
There is another hypothesis that argues the strict connection between inflammation and senescence, highlighting the role of chronic inflammation in awakening of dormant tumor cells (Manjili, 2017). Among cytokines, IFN-γ has been shown to leave antitumorigenic effects that result in arresting of cell cycle and induction of dormancy in indolent tumor cells (Aqbi et al., 2018b). NMs featuring tailored chemical properties have been used for delivering IFN-γ to tumor cells (Mejías et al., 2011). Yet, the beneficial antitumor activity of this pleiotropic lymphokine might be autophagy-independent, since little has been reported regarding this matter. Most recently, scientists developed a novel chemo-immuno strategy toward targeted delivery of agents with high antitumor and/or antifibrotic potency, celastrol and mitoxantrone. In their study, mitoxantrone-responsive nanocarriers successfully curtailed the proliferation of tumor cells and further suppressed tumor invasion. The affected tumor cells remained dormant long after cotreatment with both agents, causing a sustained progression-free survival of the mice affected with desmoplastic melanoma (Liu et al., 2018a).
Nanocarriers were also used for the efficient delivery of dormancy-associated miRNAs to tumor cells. To this end, a group of scientists opted to prepare aminated polyglycerol dendritic nanocarriers for delivering miR-200c, miR-34a, and miR-93 into MG-63 and Saos-2 osteosarcoma tumor cells. Hence, using nanomaterial-mediated delivery of microRNAs associated with tumor-host interactions might be a useful strategy to induce a dormant-like state (Tiram et al., 2016).
Autophagy Mediated Multiple Drug Resistance in Chemotherapy of Cancer Cells
Characterized by the gradual development of resistance to multiple chemotherapeutic agents with different mechanisms of action by tumor cells, multidrug resistance (MDR) is an undesirable outcome of chemotherapy that may occur in several instances (Holohan et al., 2013). A major culprit responsible for a significant proportion of cancer-associated mortality, MDR commonly results in the failure of treatment. A strikingly important challenge in cancer therapy, MDR, along with tumorigenesis, were previously thought to be correlated with disruptions in the regulation of autophagy. The idea came to fruition once several investigations reported potential involvement of autophagic pathways in the emergence of MDR (Kumar et al., 2012; Liu et al., 2020).
According to the recent findings, autophagy may affect MDR through a number of mechanisms, as explained below (Li et al., 2017):
Autophagy can prompt MDR as a cytoprotective mechanism (Table 4).
- Autophagy is positively correlated with development of MDR.
- Inhibition of autophagy may enhance the effectiveness of chemotherapy in cases with MDR.
Autophagy, when resulting in cell death, can overcome MDR (Table 4).
Autophagy triggers cell death in apoptosis-deficient MDR tumor cells.
Autophagy accelerates chemosensitization.
Induced by many cancer therapies, autophagy has been suggested to improve the survival of tumor cells and facilitate the development of MDR (Kondo et al., 2005; Amaravadi et al., 2011; Levy et al., 2017; Smith and Macleod 2019). For example, resistance to enzalutamide was counteracted by inhibition of autophagy in an investigation on prostate cancer (Nguyen et al., 2014). Likewise, in one study, inhibition of autophagy in estrogen receptor–positive breast cancer resulted in sensitization of the resistant tumor cells to the cytotoxic effects of tamoxifen (Qadir et al., 2008; Samaddar et al., 2008). Autophagy was also reported to be activated in response to imanitinib, used for the treatment of gastrointestinal stromal tumor. In this particular case, chloroquine (CQ) was adopted to overcome autophagy and trigger apoptosis in tumor cells (Gupta et al., 2010). A growing body of evidence suggests that autophagy is induced in response to many types of cancer therapy, hence the development of MDR (Galluzzi et al., 2017).
Disinhibition of autophagy is often suggested to be a consequence of low mTOR activity and is most commonly observed with therapies that target mTOR, PI3K, or AKT (Amaravadi et al., 2011). Nonetheless, one cannot certainly predict the induction of autophagy, since the extent of induction may vary in conventional and nonconventional therapies. An increased p53 activity triggered by DNA damage due to genotoxic therapeutics such as cisplatin may partly explain the undesirable induction of autophagy in conventional treatments that occur as a result of the increased activity of p53-dependent regulators of autophagy, e.g., DRAM1 (Crighton et al., 2006). Nevertheless, the exact role of p53 in this context is debatable, since this tumor-suppressing protein can also inhibit autophagy (Simon et al., 2017). Known to stimulate the activity of autophagy-regulating genes—namely, ATG5, LC3, etc.—the induction of ATF4 and forkhead box class O transcription factors due to ER stress response and overproduction of ROS, respectively, may explain the activation of autophagy in these instances (Ranganathan et al., 2006; Warr et al., 2013). The dual proapoptotic/antiapoptotic roles of autophagy largely depend on the characteristics of tumors. In the case of MDR cancer, exerts a protective effect on tumor cells by facilitating resistance to chemotherapeutic agents. Accordingly, inhibition of autophagy might be an effective strategy to sensitize MDR tumor cells to anticancer therapies. Nonetheless, more recent evidence suggests otherwise by pointing to the unappreciated potential of autophagy at sensitizing MDR tumor cells to anticancer agents and reversing MDR. Should this be the case, autophagy will inspire development of promising therapeutic modalities to overcome MDR (Li et al., 2017). Table 4 represents the studies on the prosurvival and prodeath role of autophagy in MDR of chemotherapy [updated from Li et al., (2017) and Das et al. (2019)].
The studies on the prosurvival and prodeath role of autophagy in MDR of chemotherapy
Conclusion and Outlook
As of this date, the exact molecular pathways involved in modulation of autophagy and their significance in tumor formation and progression are not clearly understood. However, as scientists suggest, autophagy is not an immutable constituent but rather a dynamic mechanism with quite varied behavior in cell biology. We ought to clarify that, because of the double-edged nature of autophagy, this regulatory mechanism can either result in induction or suppression of tumorigenesis depending on the type and stage of tumor. An increasing number of investigations have pointed to the impact of activated autophagy on the fate of tumor cells. From one point of view, autophagy might serve as an impeccable cellular shield against tumorigenesis, which can be adopted into therapeutic strategies. On the contrary, however, the exact same phenomenon might bring about further formation of tumors, with catastrophic consequences if provoked at will—namely, secondary metastasis and tumor relapse. Nevertheless, pharmacological modulation of autophagy has allegedly led to satisfactory results in limited research areas that could imply the potential of such interventions in development of novel therapeutics for cancer treatment. In this regard, scientists have less frequently discussed the potential effects of nanomaterials in mediation of autophagy.
Recently, newly emerging technologies have provided us with convenient methods for materialization of highly specialized nanoparticles for a variety of therapeutic purposes. Much to our dismay, however, the gross production of nanoparticles has led to an incontrovertible risk of exposure for people, prompting close studies of potentially harmful effects that might be conveyed through these tiny particles. Hopefully, an expansive array of information on the process of cellular uptake of nanoparticles has been gathered, indicating that the rate of cellular internalization is possible to be controlled based on physicochemical properties of nanoparticles, i.e., size, charge, and surface properties. It is anticipated that a thorough understanding of the functional interactions between autophagy and nanoparticles will tremendously impact the design of nanomaterials in such a way that development of tunable and safe nanomaterials will no longer be a far-fetched vision.
As for nanoparticles in this respect, several concerns still remain regarding the effect of different nanoparticles on the activation/suppression of autophagy, since it can very well lead to induction/inhibition of proliferation, differentiation, and invasiveness of tumor cells. According to many studies, nanomaterials can affect autophagy in malignant cells in such a way that can be adopted for development of therapeutic modalities for treatment of this malady. For instance, in a recent investigation (which is currently in press), we demonstrated the prominent role of gold nanoparticles applied through photothermal therapy in determining the destiny of tumor cells by means of regulating autophagy. In a similar fashion, in the present paper, we have sought to advise the scientists investigating in these particular fields of these concerns. That is to say, modulation of autophagy through nanomaterials is thought to be of therapeutic value for suppressing tumorigenesis in normal tissues and initiation of alternative cell death in compromised cells that struggle to properly kill themselves, on top of which stand malignant cells. This type of intervention can be further complemented by combining with traditional antitumor regimens to achieve a higher level of efficacy.
The complex interaction of autophagy-related pathways with the immune cells is another factor that might determine the fate of a tumor cell. Better understanding of the molecular pathways underlying the immune escape in recent years has accelerated the development of novel immunotherapies that aim to target molecules that would otherwise counteract the desirable antitumor immune response. Recent investigations have also highlighted the regulatory effects of autophagy on immunity through modulation of cytokine release and the function of immune cells. In return, a number of cytokines and certain types of immune cells reciprocate by affecting the autophagy itself. Accordingly, autophagy can very well be adopted for development of novel therapeutic approaches when combined with tumor immunotherapy and even nanobiotechnology.
An increasing research interest in autophagy and autophagy-related cell death is evidence enough to the significance of this matter. Since the mechanism is of both physiologic and pathologic prominence, it would be best if autophagy were approached from both academic and clinical aspects. One crucial task in this field is to identify new biomarkers and develop novel tests to precisely determine the dynamic processes of autophagy in real-life samples. It is expected that such efforts will help us better understand how autophagy is modulated within tumor cells and ameliorate the design of clinical approaches aimed at targeting this mechanism. Prospective efforts should focus more on unraveling the genetic and physiologic grounds of autophagy, which would most likely improve the therapeutic value of our knowledge regarding this type of cell death.
Authorship Contributions
Participated in research design: Ghaznavi, Sheervalilou.
Wrote or contributed to the writing of the manuscript: Ghaznavi, Shirvaliloo, Zarebkohan, Shams, Radnia, Bahmanpour, Sargazi, Saravani, Shirvalilou, O. Shahraki, S. Shahraki, Nazarlou, Sheervalilou.
Note Added in Proof: The title of this article was changed from that used for the Fast Forward version published May 18, 2021.
Footnotes
- Received January 7, 2021.
- Accepted April 19, 2021.
↵1 H.G., O.S., and R.S. contributed equally.
This work was supported by the Zahedan University of Medical Sciences [IR.ZAUMS.REC.1399.437].
The authors declare that they have no conflict of interest.
Abbreviations
- Akt
- protein kinase B
- ARHI
- aplysia ras homolog I
- ATG
- autophagy-related gene
- Bak1
- Bcl2 antagonist killer
- Bax
- BCL2 associated X
- Bcl2
- B-cell lymphoma 2
- beclin 1
- a mammalian homolog of yeast Atg6 encoded by the BECN1 gene
- Bid
- BH3 interacting domain death agonist
- Bif-1
- Bax-interacting factor 1
- Chemo-PTT
- chemotherapy with photothermal therapy
- CNT
- carbon nanotube
- CQ
- chloroquine
- CVT
- cytoplasm vacuole targeting
- DRAM
- damage-regulated autophagy modulator
- EGFR
- epidermal growth factor receptor
- EMT
- epithelial-to-mesenchymal transition
- ER
- endoplasmic reticulum
- GCMSNs
- GNPs-capped mesoporous silica nanoparticle
- HER2
- human epidermal growth factor receptor 2
- IFN
- interferon
- IONP
- iron oxide nanoparticle
- LC3
- microtubule-associated protein light chain 3
- 3-MA
- 3-methyladenine
- miRNA
- micro RNA
- MDR
- multidrug resistance
- MSN
- mesoporous silica nanoparticle
- mTOR
- mammalian target of rapamycin
- ND
- nanodiamond
- NM
- nanomaterial
- NP
- nanoparticle
- PERK
- protein endoplasmic reticulum kinase
- PI3K
- phosphatidylinositol 3-kinase
- PLGA
- poly(lactic-coglycolic acid)
- PTT
- photothermal therapy
- QD
- quantum dot
- ROS
- reactive oxygen species
- TNF
- tumor necrosis factor
- Tor
- target of rapamycin
- TRAIL
- TNF-related apoptosis-inducing ligand
- ZnO NP
- Zinc oxide nanoparticle
- Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
References
In this issue
Jump to section
- Article
- Abstract
- Introduction
- Autophagy: Involved Pathways
- Apoptosis
- Autophagy and Apoptosis: Possible Links and Differences
- Can Autophagy Hinder or Aggravate Cancer?
- Nanotechnology
- The Link between Autophagy and Nanotechnology
- Effects of NMs on Tumor Dormancy: Focusing on Involved Signaling Pathways
- Autophagy Mediated Multiple Drug Resistance in Chemotherapy of Cancer Cells
- Conclusion and Outlook
- Authorship Contributions
- Footnotes
- Abbreviations
- References
- Figures & Data
- Info & Metrics
- eLetters