Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewAutophagy is a therapeutic target in anticancer drug resistance
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).
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