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.
Highlights
Our findings suggest that various apoptosis defects that block TRAIL-mediated cell death at different points along the apoptotic signaling pathway shift the signaling cascade toward cell-protective autophagy
The current studies demonstrate the involvement of protective autophagy in response to TRAIL of tumor cells with various apoptotic defects
The possibility of potentially inhibited the apoptotic response to TRAIL of BaxϪ/Ϫ Hct116 reversing multiple mechanisms of TRAIL resistance by the cells that was enabled by beclin-1 RNAi (Fig. 8A)
Summary
Z, benzyloxycarbonyl; IL, interleukin; 3MA, 3-methyladenine; DISC, death-inducing signaling complex; Ab, antibody; DAPI, 4Ј,6-diamidino-2-phenylindole; fmk, fluoromethyl ketone; TUNEL, terminal dUTP nick-end labeling; RNAi, RNA interference; WT, wild type; MOPS, 4-morpholinepropanesulfonic acid; TRAIL-R, TRAIL receptor. Reversal of TRAIL Resistance by Autophagy Inhibition accelerated apoptotic cell death, characterized by activation of caspases, mitochondrial permeabilization, and chromatin condensation [9, 10]. Multiple studies have demonstrated that a variety of apoptotic agents and proteins sensitize several classes of tumor cells to TRAIL-induced apoptosis [13, 15]. We propose that divergent mechanisms of resistance to TRAIL-mediated apoptosis can be reversed by a common approach of targeting for inhibition-specific components of the autophagic process. This novel concept may have significant implications for the development of new strategies to circumvent TRAIL resistance in tumors
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