Review
Autophagy is a therapeutic target in anticancer drug resistance

https://doi.org/10.1016/j.bbcan.2010.07.003Get rights and content

Abstract

Autophagy is a type of cellular catabolic degradation response to nutrient starvation or metabolic stress. The main function of autophagy is to maintain intracellular metabolic homeostasis through degradation of unfolded or aggregated proteins and organelles. Although autophagic regulation is a complicated process, solid evidence demonstrates that the PI3K-Akt-mTOR, LKB1-AMPK-mTOR and p53 are the main upstream regulators of the autophagic pathway. Currently, there is a bulk of data indicating the important function of autophagy in cancer. It is noteworthy that autophagy facilitates the cancer cells' resistance to chemotherapy and radiation treatment. The abrogation of autophagy potentiates the re-sensitization of therapeutic resistant cancer cells to the anticancer treatment via autophagy inhibitors, such as 3-MA, CQ and BA, or knockdown of the autophagy related molecules. In this review, we summarize the accumulation of evidence for autophagy's involvement in mediating resistance of cancer cells to anticancer therapy and suggest that autophagy might be a potential therapeutic target in anticancer drug resistance in the future.

Introduction

Autophagy, also called macroautophagy, is a kind of cellular catabolic degradation response to nutrient starvation or metabolic stress [1], [2], [3]. During the initial stages of autophagic process, cellular proteins, organelles and cytoplasm are sequestered and engulfed by the intracellular double-membrane-bound structures, called autophagosomes (early autophagic vesicles) [1], [2], [4], [5]. These autophagosomes mature by fusing with lysosomes to form the autolysosomes (late autophagic vesicles) [2], [4], [5], [6], [7], [8], in which the sequestered proteins and organelles are digested by lysosomal hydrolases and recycled to sustain cellular metabolism [9], [10], [11], [12], [13].

Whenever we talked about autophagy, we had to refer to apoptosis (process of programmed cell death), which shared several common regulatory elements with autophagy [14], [15], [16]. Autophagy was believed as a non-apoptotic programme of cell death or “type-II” cell death to distinguish with apoptosis [17]. Under most circumstances, autophagy promoted cell survival by adapting cells to the stress conditions, which was functionally paradoxical to apoptosis. However, it is still fundamentally important to clarify whether autophagy is a main strategy for cell survival, or if it also serves as a trigger for cell death [17].

Autophagy is an evolutionarily conserved process from yeast to mammals [3], [18], [19]. The main function of autophagy is to maintain intracellular metabolic homeostasis. In parallel with the ubiquitin proteasome degradation pathway, the dynamic autophagic process supervises and maintains the protein and organelle quality control to prevent the accumulation of unfolded and aggregated proteins [6], [7], [8], [11], [13]. In addition to this key function, autophagy was also found to be responsible for other important functions, especially under stressful situation [18], [20], [21]. Whenever faced with environmental stressors, such as metabolic deprivation DNA damage caused by chemotherapy or radiation and hypoxia, the process of autophagy is activated which leads to cell survival or death [2], [18], [22], [23], [24], [25], [26], [27].

There is an accumulation of evidence that highlights the important function of autophagy in cancer [2], [5], [22], [23], [24], [25], [28]. Although it is still controversial about whether autophagy kills cancer cells or sustains their survival under stressful conditions, more and more reports provide data to support that autophagy promotes cancer cell survival after chemotherapy or radiation therapy [22], [29], [30]. For example, autophagy facilitates resistance chronic myeloid leukemia (CML) to Imatinib mesylate (IM) [31], and also potentiates resistance of HER2 positive breast cancer cells to anti-HER2 monoclonal antibody trastuzumab [32]. Intriguingly, abrogation of autophagy by autophagy inhibitors, such as 3-MA, CQ and BA, or by shRNA knockdown of autophagy related molecules, re-sensitizes the resistant cancer cells to the chemotherapy or radiation [30], [31]. It is also noteworthy that the autophagic inhibitor hydroxychloroquine (HCQ) has already been applied in a clinical trial. So, it is possible to expect autophagic inhibitors to be the next generation of drugs to overcome anticancer therapeutic resistance. Herein, in this review, we will discuss the state-of-art of the molecular regulation mechanisms of autophagy, autophagy function in cancer, and emphasize the facilitation of autophagic inhibition in anticancer drug resistance.

Section snippets

Molecular regulation mechanism of autophagy in cancer

Autophagy is a complicated regulatory process, which involves a great number of upstream regulating signaling pathways [2], [22], [28]. Nevertheless, no matter it is normal or cancer cells, the mammalian target of rapamycin (mTOR) serves as the main regulator of autophagy [22], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43]. In response to nutrient availability, mTOR activation suppresses autophagy and stimulates cell proliferation. However, under nutrient deprivation,

Double face of autophagy's function in cancer

Although the regulatory mechanism of autophagy is partially manifested, however, the function of autophagy in cancer is still in an undetermined debate. Whether autophagy is a death-induced mechanism or a protective effort for cellular survival is still a controversy [1], [2]. There are a number of evidences to support the double-faced function of autophagy in cancer: tumor suppression and also promotion.

Autophagy confers the anticancer drug resistance

Adjuvant cancer treatment, such as chemotherapy or radiotherapy, etc., is very important to prevent or postpone the cancer’s relapse and prolong the patients' survival. However, one of the most daunting clinical problems is the frequent relapse after the treatment even with longer dormancy [2], [118]. Most of the therapeutic failures are due to the intrinsic or acquired resistance towards the therapy. Presumably, autophagy is one of the most important mechanisms to enable cancer cells' survival

Concluding remarks

One of the most daunting clinical issues is the frequent tumors progression after standard treatment, mainly due to therapeutic resistance. It is urgent to elucidate the mechanisms that induce anticancer drug resistance. As we discussed in this review, although the controversy about the pro- or anticancer effect of autophagy is still heated, the in vitro and in vivo data fully support that autophagy can facilitate the tumor cells' survival to anticancer treatment [2], [4], [21], [55], [56],

Acknowledgments

The authors would like to acknowledge support from Chinese National Key Basic Research & Development Program (2009CB521704).

References (183)

  • M. Tanemura et al.

    Rapamycin induces autophagy in islets: relevance in islet transplantation

    Transplant. Proc.

    (2009)
  • Z. Luo et al.

    AMPK, the metabolic syndrome and cancer

    Trends Pharmacol. Sci.

    (2005)
  • A.V. Budanov et al.

    p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling

    Cell

    (2008)
  • A. Woods et al.

    LKB1 is the upstream kinase in the AMP-activated protein kinase cascade

    Curr. Biol.

    (2003)
  • K.A. Anderson et al.

    Hypothalamic CaMKK2 contributes to the regulation of energy balance

    Cell Metab.

    (2008)
  • O. Krejci et al.

    p53 signaling in response to increased DNA damage sensitizes AML1-ETO cells to stress-induced death

    Blood

    (2008)
  • T. Yamaguchi et al.

    Protein kinase C delta activates IkappaB-kinase alpha to induce the p53 tumor suppressor in response to oxidative stress

    Cell. Signal.

    (2007)
  • D. Crighton et al.

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

    Cell

    (2006)
  • D.R. Green et al.

    p53 and metabolism: Inside the TIGAR

    Cell

    (2006)
  • V.M. Aita et al.

    Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21

    Genomics

    (1999)
  • S. Pattingre et al.

    Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy

    Cell

    (2005)
  • J.J. Lum et al.

    Autophagy in metazoans: cell survival in the land of plenty

    Nat. Rev. Mol. Cell Biol.

    (2005)
  • R. Mathew et al.

    Role of autophagy in cancer

    Nat. Rev. Cancer

    (2007)
  • Y. Kondo et al.

    The role of autophagy in cancer development and response to therapy

    Nat. Rev. Cancer

    (2005)
  • S. Jin et al.

    Role of autophagy in cancer: management of metabolic stress

    Autophagy

    (2007)
  • Z. Yang et al.

    An overview of the molecular mechanism of autophagy

    Curr. Top. Microbiol. Immunol.

    (2009)
  • Y.P. Yang et al.

    Molecular mechanism and regulation of autophagy

    Acta Pharmacol. Sin.

    (2005)
  • C.W. Wang et al.

    The molecular mechanism of autophagy

    Mol. Med.

    (2003)
  • T. Hara et al.

    Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice

    Nature

    (2006)
  • M. Komatsu et al.

    Loss of autophagy in the central nervous system causes neurodegeneration in mice

    Nature

    (2006)
  • M. Komatsu et al.

    Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice

    J. Cell Biol.

    (2005)
  • B. Ravikumar et al.

    Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy

    Hum. Mol. Genet.

    (2002)
  • M.C. Maiuri et al.

    Self-eating and self-killing: crosstalk between autophagy and apoptosis

    Nat. Rev. Mol. Cell Biol.

    (2007)
  • J.M. Vicencio et al.

    Senescence, apoptosis or autophagy? When a damaged cell must decide its path—a mini-review

    Gerontology

    (2008)
  • A. Rami

    Review: autophagy in neurodegeneration: firefighter and/or incendiarist?

    Neuropathol. Appl. Neurobiol.

    (2009)
  • D.J. Klionsky et al.

    Autophagy as a regulated pathway of cellular degradation

    Science

    (2000)
  • S. Yousefi et al.

    Autophagy in cancer and chemotherapy

    Results Probl. Cell Differ.

    (2009)
  • V. Karantza-Wadsworth et al.

    Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis

    Genes Dev.

    (2007)
  • V. Karantza-Wadsworth et al.

    Role of autophagy in breast cancer

    Autophagy

    (2007)
  • B. Levine

    Unraveling the role of autophagy in cancer

    Autophagy

    (2006)
  • S.L. Lomonaco et al.

    The induction of autophagy by gamma-radiation contributes to the radioresistance of glioma stem cells

    Int. J. Cancer

    (2009)
  • I. Papandreou et al.

    Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L

    Cell Death Differ.

    (2008)
  • N. Chen et al.

    Autophagy and tumorigenesis

    FEBS Lett.

    (2009)
  • A. Apel et al.

    Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy

    Cancer Res.

    (2008)
  • C. Bellodi et al.

    Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells

    J. Clin. Invest.

    (2009)
  • A. Vazquez-Martin et al.

    Autophagy facilitates the development of breast cancer resistance to the anti-HER2 monoclonal antibody trastuzumab

    PLoS ONE

    (2009)
  • L. Qin et al.

    ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy

    Autophagy

    (2010)
  • C.H. Jung et al.

    mTOR regulation of autophagy

    FEBS Lett.

    (2010)
  • K.C. Choi et al.

    A novel mTOR activating protein protects dopamine neurons against oxidative stress by repressing autophagy related cell death

    J. Neurochem.

    (2010)
  • J.M. Rosenbluth et al.

    mTOR regulates autophagy-associated genes downstream of p73

    Autophagy

    (2009)
  • Cited by (332)

    View all citing articles on Scopus
    View full text