Review
Autophagy regulation and its role in cancer

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Abstract

The modulation of macroautophagy is now recognized as one of the hallmarks of cancer cells. There is accumulating evidence that autophagy plays a role in the various stages of tumorigenesis. Depending on the type of cancer and the context, macroautophagy can be tumor suppressor or it can help cancer cells to overcome metabolic stress and the cytotoxicity of chemotherapy. Recent studies have shed light on the role of macroautophagy in tumor-initiating cells, in tumor immune response cross-talk with the microenvironment. This review is intended to provide an up-date on these aspects, and to discuss them with regard to the role of the major signaling sub-networks involved in tumor progression (Beclin 1, MTOR, p53 and RAS) and in regulating autophagy.

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 ATG12ā€“ATG5-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 ā€˜the ligue nationale contre le cancerā€™.

References (296)

  • A. Efeyan et al.

    mTOR and cancer: many loops in one pathway

    Current Opinion in Cell Biology

    (2010)
  • L. Ma et al.

    Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis

    Cell

    (2005)
  • S.F. Funderburk et al.

    The Beclin 1-VPS34 complexā€”at the crossroads of autophagy and beyond

    Trends in Cell Biology

    (2010)
  • S. Pattingre et al.

    Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy

    Cell

    (2005)
  • Y. Wei et al.

    JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy

    Molecular Cell

    (2008)
  • S. Pattingre et al.

    Role of JNK1-dependent Bcl-2 phosphorylation in ceramide-induced macroautophagy

    Journal of Biological Chemistry

    (2009)
  • J. Kim et al.

    Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy

    Cell

    (2013)
  • S. Luo et al.

    Bim inhibits autophagy by recruiting beclin 1 to microtubules

    Molecular Cell

    (2012)
  • B.D. Manning et al.

    AKT/PKB signaling: navigating downstream

    Cell

    (2007)
  • T. Furuya et al.

    Negative regulation of Vps34 by Cdk mediated phosphorylation

    Molecular Cell

    (2010)
  • M.C. Maiuri et al.

    Autophagy regulation by p53

    Current Opinion in Cell Biology

    (2010)
  • D. Crighton et al.

    DRAM, a p53-induced modulator of autophagy, is critical for apoptosis

    Cell

    (2006)
  • B. Harrison et al.

    DAPK-1 binding to a linear peptide motif in MAP1B stimulates autophagy and membrane blebbing

    Journal of Biological Chemistry

    (2008)
  • J. Pimkina et al.

    ARF induces autophagy by virtue of interaction with Bcl-xl

    Journal of Biological Chemistry

    (2009)
  • K. Bensaad et al.

    TIGAR, a p53-inducible regulator of glycolysis and apoptosis

    Cell

    (2006)
  • J. Liu et al.

    Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13

    Cell

    (2011)
  • M. Elgendy et al.

    Oncogenic Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death and limits clonogenic survival

    Molecular Cell

    (2011)
  • M.J. Kim et al.

    Involvement of autophagy in oncogenic K-Ras-induced malignant cell transformation

    Journal of Biological Chemistry

    (2011)
  • G. Marino et al.

    Autophagy in Ras-induced malignant transformation: fatal or vital

    Molecular Cell

    (2011)
  • B. Ravikumar et al.

    Regulation of mammalian autophagy in physiology and pathophysiology

    Physiological Reviews

    (2010)
  • N. Mizushima et al.

    The role of Atg proteins in autophagosome formation

    Annual Review of Cell and Developmental Biology

    (2011)
  • H.E. Polson et al.

    Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation

    Autophagy

    (2010)
  • A. Simonsen et al.

    Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes

    Journal of Cell Biology

    (2009)
  • A.M. Choi et al.

    Autophagy in human health and disease

    New England Journal of Medicine

    (2013)
  • V. Deretic

    Autophagy: an emerging immunological paradigm

    Journal of Immunology

    (2012)
  • S. Pattingre et al.

    Bcl-2 inhibition of autophagy: a new route to cancer

    Cancer Research

    (2006)
  • J. Botti et al.

    Autophagy signaling and the cogwheels of cancer

    Autophagy

    (2006)
  • M.C. Maiuri et al.

    Control of autophagy by oncogenes and tumor suppressor genes

    Cell Death and Differentiation

    (2009)
  • E.Y. Liu et al.

    Autophagy and cancerā€”issues we need to digest

    Journal of Cell Science

    (2012)
  • B. Levine

    Cell biology: autophagy and cancer

    Nature

    (2007)
  • E. White

    Deconvoluting the context-dependent role for autophagy in cancer

    Nature Reviews Cancer

    (2012)
  • W.K. Wu et al.

    The autophagic paradox in cancer therapy

    Oncogene

    (2012)
  • M. Laplante et al.

    mTOR signaling

    Cold Spring Harbor Perspectives in Biology

    (2012)
  • R. Zoncu et al.

    mTOR: from growth signal integration to cancer, diabetes and ageing

    Nature Reviews Molecular Cell Biology

    (2011)
  • C. Mammucari et al.

    Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscle

    Autophagy

    (2008)
  • C.H. Jung et al.

    ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery

    Molecular Biology of the Cell

    (2009)
  • R.C. Wang et al.

    Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation

    Science

    (2012)
  • S.M. McBride et al.

    Activation of PI3K/mTOR pathway occurs in most adult low-grade gliomas and predicts patient survival

    Journal of Neuro-Oncology

    (2010)
  • N.B. Ruderman et al.

    AMPK and SIRT1: a long-standing partnership

    American Journal of Physiology ā€“ Endocrinology and Metabolism

    (2010)
  • M. Buzzai et al.

    Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth

    Cancer Research

    (2007)
  • Cited by (0)

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