ReviewAutophagy regulation and its role in cancer
Introduction
The word autophagy, from the Greek self-eating, refers to the catabolic processes through which the cell recycles its own constituents [1]. The proteasome is also involved in cell degradation, but the term autophagy is used solely to refer to the pathways that lead to the elimination of cytoplasmic components by delivering them into lysosomes. To date, three major types of autophagy have been described: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) [1], [2]. This review will focus on macroautophagy (hereafter referred to simply as autophagy), because the evidence that the other forms of autophagy play any role in tumor biology is relatively limited [1]. Macroautophagy starts with the formation of a doubled-membrane bound vacuole, known as the autophagosome, that engulfs fractions of the cytoplasm in an either unselective or selective manner via the activity of the autophagy adaptors (SQSTM1/p62, NBR1, NDP52 and optineurin) that form a bridge between the target and the growing autophagosome membrane [1], [2]. After being formed, most autophagosomes receive input from the endocytic vesicles to form an amphisome, in which the autophagic cargo is degraded and delivered into the lysosomal lumen [1]. At its basal rate, autophagy exercises quality control of the cytoplasm of most cells by removing damaged organelles and protein aggregates [1], [2], [3]. Autophagy responds to a range of stimuli, and in most cases protects cells against stressful situations [1], [2], [3]. In response to starvation, autophagy is important for the lysosomal recycling of metabolites to the cytoplasm, where they are reused either as source of energy or to provide building blocks for the synthesis of new macromolecules.
The discovery of ATGs (autophagy-related genes) in eukaryotic cells, and that of the role of ATG proteins in the formation of autophagosomes were milestones in the understanding of the molecular aspects of autophagy, and of the source of the membrane involved in the assembly of ATG proteins to form the phagophore, the isolation membrane that subsequently elongates to form the autophagosome [2], [4], [5]. At a molecular level, the first step in the initiation of autophagy is the activation of a molecular complex containing the serine/threonine kinase ULK1 (the mammalian ortholog of Atg1 in yeast) [4]. The activation of this complex is down-regulated by MTORC1, which integrates multiple signaling pathways that are sensitive to the availability of amino acids, ATP, growth factors, level of ROS. The expansion, curvation and closure of the autophagosome are controled by another molecular complex containing phosphatidylinositol 3-kinase (PI3K) and Beclin 1 (the mammalian orthologue of Atg6 in yeast), which allows the production of phosphatidylinositol 3-phosphate (PI3P) to occur, and the subsequent recruitment of PI3P-binding proteins WIPI1/2 [6] and two ubiquitin-like conjugation systems ATG12āATG5-ATG16L and LC3-PE. The final fusion with lysosome requires small Rab GTPases and the transmembrane protein LAMP2 [7]. Acid hydrolases and the cathepsins present in the lysosomal lumen degrade the autophagosomal cargoes.
Advances in our understanding of the autophagic process paved the way for the discovery of the importance of autophagy in development, tissue homeostasis, metabolism, the immune response and various disease [2], [8], [9]. Interest in the role of autophagy in cancer stems from the discovery that BECN1 (the gene that encodes Beclin 1) is also a haplo-insufficient tumor suppressor gene [10]. In fact, it appears that autophagy is under the control of a large panel of oncogenes and products of tumor suppressor genes [11], [12]. However, the role of autophagy in tumors is complex and ranges from a tumor suppressive role to a role in adapting to the environment [13], [14], [15], [16]. This review will summarize what we know about the various aspects of autophagy in cancer, and present the emerging role of autophagy in cancer stem cells, in cancer cell dormancy and in the cross-talk between cancer cells and the microenvironment.
Section snippets
Regulation of autophagy by tumor suppressors and oncogene networks
Autophagy is under the control of tumor suppressors and oncogenes. Tumor suppressors have a stimulatory effect on autophagy, whereas oncogenes down-regulate it. In this section, we focus on two tumor suppressor networks (MTOR and Beclin 1) that control the very early stage of autophagy. We also discuss the role of p53 and RAS in autophagy, because the role of these proteins in autophagy is context- and location-dependent (Fig. 1). Readers interested in a more detailed discussion of the role of
Overview of the role of autophagy in cancer
In cancer cells, autophagy fulfills a dual role, having both tumor-promoting and tumor-suppressing properties (Fig. 2). By maintaining cellular homeostasis in healthy cells, autophagy prevents DNA damage and genomic instability, which can lead to tumoral transformation. Autophagy can also facilitate oncogene-induced senescence or protect tumors against necrosis and inflammation, thus limiting tumor growth. On the other hand, autophagy can contribute to tumor progression, by allowing tumor cells
Autophagy within the tumoral environment
Accumulating evidence now indicates that tumor development (in particular that of solid tumors) relies on continuous cross-talk between cancer cells and their cellular and extracellular microenvironments (for reviews, see [165], [166]). The tumor stroma is made up of diverse cell populations including macrophages, lymphocytes, vascular cells, and carcinoma-associated fibroblasts providing growth factors, inflammatory cytokines, angiogenic factors, and elements of the extracellular matrix. Thus,
Therapeutic modulation of autophagy in cancer
Besides its evolutionarily conserved role in promoting cell survival during metabolic stress, autophagy also plays an essential role in determining how tumor cells respond to therapy and changing environmental stimuli. Table 3 summarizes the numerous studies that have investigated the modulation of autophagy in various types of solid and hematological malignancies by different forms of cancer therapy including radiation [208] or chemotherapeutic drugs and immunotherapy such as vitamin D
Conclusion and future prospects
As our understanding of the biological functions of autophagy increases, the involvement of autophagy in cancer is becoming a critical point of concern. Here we have attempted to review some of the emerging issues surrounding the relationship between autophagy and tumorigenesis. The molecular cross-talk between autophagy and cell death was initially thought to be a major determinant of the balancing role of autophagy between tumor suppression and tumor progression [221]. Studies intended to
Funding
S. Lorin's work is supported by institutional funding from the UniversitĆ© Paris-Sud and that of A. HamaĆÆ, M. Mehrpour and P. Codogno by institutional funding from the Institut National de la SantĆ© et de la Recherche Medicale (INSERM), grants from the Agence Nationale de la Recherche (ANR),the Institut National du Cancer (INCa) and āthe ligue nationale contre le cancerā.
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