Elsevier

Biochemical Pharmacology

Volume 82, Issue 5, 1 September 2011, Pages 427-434
Biochemical Pharmacology

Commentary
Autophagy as a mediator of chemotherapy-induced cell death in cancer

https://doi.org/10.1016/j.bcp.2011.06.015Get rights and content

Abstract

Since the 1940s, chemotherapy has been the treatment of choice for metastatic disease. Chemotherapeutic agents target proliferating cells, inducing cell death. For most of the history of chemotherapy, apoptosis was thought to be the only mechanism of drug-induced cell death. More recently, a second type of cell death pathway has emerged: autophagy, also called type II programmed cell death. Autophagy is a tightly regulated process by which selected components of a cell are degraded. It primarily functions as a cell survival adaptive mechanism during stress conditions. However, persistent stress can also promote extensive autophagy, leading to cell death, hence its name. Alterations in the autophagy pathway have been described in cancer cells that suggest a tumor-suppressive function in early tumorigenesis, but a tumor-promoting function in established tumors. Moreover, accumulating data indicate a role for autophagy in chemotherapy-induced cancer cell death. Here, we discuss some of the evidence showing autophagy-dependent cell death induced by anti-neoplastic agents in different cancer models. On the other hand, in some other examples, autophagy dampens treatment efficacy, hence providing a therapeutic target to enhance cancer cell killing. In this paper, we propose a putative mechanism that could reconcile these two opposite observations.

Section snippets

Autophagy: an introduction

Autophagy is a self-degradative process that enables cells to cope with stresses such as nutrient deprivation, ER stress, pathogen infection or hypoxia. Autophagy is thus generally considered to be a survival mechanism. On the other hand, when the severity or the duration of the stress is too long, or in apoptotic-deficient cells, autophagy may participate in cell death. Therefore, it has been called type II programmed cell death (type I being apoptosis itself). The role of autophagy in cell

Role of autophagy in cancer

Alterations in the autophagy pathway in cancer cells raised a paradox because autophagy functions as a tumor suppressive mechanism, but is also used by cancer cells for cytoprotection to cope with their hostile microenvironment [13], [14], [15]. This dual role of autophagy in tumor development is illustrated by the fact that colorectal cancer patients with extensive over- or underexpression of Beclin-1 have a much poorer overall survival [16].

Balance between apoptosis and autophagy for inducing cell death

In their revised version of the hallmarks of cancer, Hanahan and Weinberg added other types of cell death beyond the previously described apoptosis. In this regard, autophagy as well as necrosis is seen as contributing to and/or counteracting drug-induced apoptosis and cell death [37]. Complex crosstalk between apoptosis and autophagy has been unraveled. There is substantial evidence indicating that suppression of apoptosis induces autophagy, while autophagy inhibition causes apoptosis [38],

To provoke cell death

As described above, half of the studies show that autophagy is required for the efficient killing of tumor cells when treated with anticancer therapies. In line with these observations, researchers are working to design new drugs that would induce autophagy by themselves, and hence eliminate cancer cells [73]. Among the potential targets in autophagy, the Akt-mTOR pathway is the most investigated one. Indeed, proteins Akt, PTEN (phosphatase and tensin homolog) and mTOR, as well as some of the

Conclusion

The involvement of autophagy in chemotherapeutic agent-induced cell death is very complex. On one hand, autophagy may protect from apoptosis and hence, autophagy inhibitors have potential use as drugs to overcome anticancer therapy resistance. On the other hand, this process participates in cell death in certain circumstances. In that case, its induction may help to eradicate malignant cells. In order to reach clinical application, we must first better understand the factors that influence the

Acknowledgments

Annick Notte is a Research Fellow at FNRS (Fonds de la Recherche Scientifique, Belgium) and Lionel Leclere is a recipient of a FRIA grant (Fonds de la Recherche Scientifique, Belgium). This article presents results of the Belgian Program on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Science Policy Programming. The responsibility is assumed by its authors.

References (94)

  • K. Degenhardt et al.

    Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis

    Cancer Cell

    (2006)
  • C.M. Kenific et al.

    Autophagy and metastasis: another double-edged sword

    Curr Opin Cell Biol

    (2010)
  • C. Horbinski et al.

    Live free or die: tales of homeless (cells) in cancer

    Am J Pathol

    (2010)
  • D. Hanahan et al.

    Hallmarks of cancer: the next generation

    Cell

    (2011)
  • J.P. Cosse et al.

    BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

    Biochem Pharmacol

    (2010)
  • C.F. Zou et al.

    Re-expression of ARHI (DIRAS3) induces autophagy in breast cancer cells and enhances the inhibitory effect of paclitaxel

    BMC Cancer

    (2011)
  • X.W. Liu et al.

    HIF-1alpha-dependent autophagy protects HeLa cells from fenretinide (4-HPR)-induced apoptosis in hypoxia

    Pharmacol Res

    (2010)
  • N. Vigneswaran et al.

    Hypoxia-induced autophagic response is associated with aggressive phenotype and elevated incidence of metastasis in orthotopic immunocompetent murine models of head and neck squamous cell carcinomas (HNSCC)

    Exp Mol Pathol

    (2011)
  • J.P. Piret et al.

    Is HIF-1alpha a pro- or an anti-apoptotic protein?

    Biochem Pharmacol

    (2002)
  • J. Li et al.

    Inhibition of autophagy augments 5-fluorouracil chemotherapy in human colon cancer in vitro and in vivo model

    Eur J Cancer

    (2010)
  • W.K. Wu et al.

    Macroautophagy modulates cellular response to proteasome inhibitors in cancer therapy

    Drug Resist Updat

    (2010)
  • S. Turcotte et al.

    A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy

    Cancer Cell

    (2008)
  • S.M. Schleicher et al.

    Progress in the unraveling of the endoplasmic reticulum stress/autophagy pathway and cancer: implications for future therapeutic approaches

    Drug Resist Updat

    (2010)
  • J.S. Carew et al.

    Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance

    Blood

    (2007)
  • M. Schnekenburger et al.

    Sustained exposure to the DNA demethylating agent, 2′-deoxy-5-azacytidine, leads to apoptotic cell death in chronic myeloid leukemia by promoting differentiation, senescence, and autophagy

    Biochem Pharmacol

    (2011)
  • B.A. Chabner et al.

    Timeline: chemotherapy and the war on cancer

    Nat Rev Cancer

    (2005)
  • V.T. DeVita et al.

    A history of cancer chemotherapy

    Cancer Res

    (2008)
  • V. Pavet et al.

    Towards novel paradigms for cancer therapy

    Oncogene

    (2011)
  • M.S. Ricci et al.

    Chemotherapeutic approaches for targeting cell death pathways

    Oncologist

    (2006)
  • J. Portugal et al.

    Cell death pathways in response to antitumor therapy

    Tumori

    (2009)
  • F. Al-Ejeh et al.

    Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

    Oncogene

    (2010)
  • B. Levine et al.

    Autophagy in cell death: an innocent convict?

    J Clin Invest

    (2005)
  • C. He et al.

    Regulation mechanisms and signaling pathways of autophagy

    Annu Rev Genet

    (2009)
  • D. Glick et al.

    Autophagy: cellular and molecular mechanisms

    J Pathol

    (2010)
  • Z. Yang et al.

    An overview of the molecular mechanism of autophagy

    Curr Top Microbiol Immunol

    (2009)
  • S. Sinha et al.

    The autophagy effector Beclin 1: a novel BH3-only protein

    Oncogene

    (2008)
  • R. Mathew et al.

    Role of autophagy in cancer

    Nat Rev Cancer

    (2007)
  • M.I. Koukourakis et al.

    Beclin 1 over- and underexpression in colorectal cancer: distinct patterns relate to prognosis and tumour hypoxia

    Br J Cancer

    (2010)
  • Z. Yue et al.

    Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor

    Proc Natl Acad Sci USA

    (2003)
  • X.H. Liang et al.

    Induction of autophagy and inhibition of tumorigenesis by Beclin 1

    Nature

    (1999)
  • J. Iqbal et al.

    Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies

    Leukemia

    (2009)
  • C. Liang et al.

    Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG

    Nat Cell Biol

    (2006)
  • D. Coppola et al.

    Down-regulation of Bax-interacting factor-1 in colorectal adenocarcinoma

    Cancer

    (2008)
  • M. Hardt et al.

    Activating mutations of TOR (target of rapamycin)

    Genes Cells

    (2011)
  • R. Mathew et al.

    Autophagy suppresses tumor progression by limiting chromosomal instability

    Genes Dev

    (2007)
  • C. Fung et al.

    Induction of autophagy during extracellular matrix detachment promotes cell survival

    Mol Biol Cell

    (2008)
  • A. Giatromanolaki et al.

    Prognostic relevance of light chain 3 (LC3A) autophagy patterns in colorectal adenocarcinomas

    J Clin Pathol

    (2010)
  • Cited by (158)

    View all citing articles on Scopus
    View full text