Involvement of Protective Autophagy in TRAIL Resistance of Apoptosis-defective Tumor Cells

Abstract

Targeting TRAIL receptors with either recombinant TRAIL or agonistic DR4-or DR5-specific antibodies has been considered a promising treatment for cancer, particularly due to the preferential apoptotic susceptibility of tumor cells over normal cells to TRAIL. However, the realization that many tumors are unresponsive to TRAIL treatment has stimulated interest in identifying apoptotic agents that when used in combination with TRAIL can sensitize tumor cells to TRAIL-mediated apoptosis. Our studies suggest that various apoptosis defects that block TRAIL-mediated cell death at different points along the apoptotic signaling pathway shift the signaling cascade from default apoptosis toward cytoprotective autophagy. We also obtained evidence that inhibition of such a TRAIL-mediated autophagic response by specific knockdown of autophagic genes initiates an effective mitochondrial apoptotic response that is caspase-8-dependent. Currently, the molecular mechanisms linking disabled autophagy to mitochondrial apoptosis are not known. Our analysis of the molecular mechanisms involved in the shift from protective autophagy to apoptosis in response to TRAIL sheds new light on the negative regulation of apoptosis by the autophagic process and by some of its individual components.Accumulating evidence suggests that autophagy functions as an adaptive cell response, allowing the cell to survive bioenergetic stress via a mechanism associated with clearance of damaged organelles and the degradation of mutant or misfolded proteins (1). Certain therapeutic approaches to cancer, including radiation and cytotoxic drugs that have been known to activate apoptosis, were observed to induce autophagy in certain human cancer cell lines (2). The functional relationship between apoptosis and autophagy and the potential cross-regulation between these two processes are complex and remain to be resolved. The complexity stems partly from the findings that in certain cellular scenarios, autophagy constitutes a stress adaptation response that avoids and suppresses cell death, whereas in other cellular settings, autophagy constitutes an alternative pathway to cellular demise that is called autophagic cell death (type II cell death) (3-5). Thus, the autophagy genes beclin-1 and atg7 are required to induce nonapoptotic cell death in murine fibroblast L929 cells treated with the caspase inhibitor Z-VAD 3 (6). In addition, Atg5 and Beclin-1 are required for etoposide-and staurosporin-induced cell death in apoptosis-resistant Bax/Bak double knock-out mouse embryonic fibroblasts (7). Current evidence suggests that the removal or functional inhibition of proteins essential for the apoptotic machinery can switch a cellular stress response from apoptotic default to massive autophagy (4, 6 -8). In this regard, dogmaaltering studies were reported by Craig Thompson's group, who discovered that when apoptosis-resistant cells are exposed to stress mediated by the decreased availability of growth factor, the ensuing autophagy actually protects cells from death (8). ...

Suppression of basal autophagy reduces lung cancer cell proliferation and enhances caspase-dependent and -independent apoptosis by stimulating ROS formation

“…Our data demonstrate that inhibition of autophagy sensitizes NSCLC cells to cisplatin-induced apoptosis, which is in line with previous findings showing that the inhibition of autophagy might enhance the ability of the drugs to induce apoptosis in tumor cells. Pharmacological inhibitors of autophagy have been shown to sensitize cells to a wide range of cytotoxic stimuli including radiation therapy, 21 TRAIL, 22 the tyrosine kinase receptor inhibitor imatinib, 23 and a DNA-damaging drug temozolomide. 24 However, the molecular mechanisms of this sensitization to treatment were not studied.…”

Autophagy—A double‐edged sword in oncology

“…Especially, apoptosis-defective tumour cells can survive chemotherapy-mediated stress by invoking a protective autophagic process suggesting that autophagy may protect tumour cells against cytotoxic therapy by conferring genomic stability. 50 In contrast, prolonged activation of autophagy may lead to cell death by cellular self-degradation. Therefore, it is difficult to predict if inhibition of autophagy may sensitise resistant tumour cells to cytotoxic therapy.…”

Autophagy, senescence and tumor dormancy in cancer therapy

“…5,6 In some studies, autophagy and apoptosis have been found to exert similar levels of toxicity 7,8 while in others a blockade to protective autophagy has resulted in cytotoxicity due to apoptosis. 3,[9][10][11][12] Finally, a recent report presents evidence for apoptosis that is dependent on prior autophagy. The transient arrest and renewed tumor growth that has been interpreted as tumor dormancy by Lu et al 2 is also a common observation in other xenograft models treated with chemotherapy or radiation; 19,20 our own studies in cell culture [21][22][23] also support the concept of drug and radiation induced senescence in tumor cells that is succeeded by proliferative recovery.…”