Abstract
Purpose: Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), a member of the TNF family, can selectively induce cancer cell death while sparing normal cells. However, the application of TRAIL-based antitumor therapies has been hindered due to drug resistance. Alternol is a new compound isolated from microbial fermentation that possesses antitumor activity in different tumors. In our research, we discovered that alternol can sensitize TRAIL-induced apoptosis in renal carcinoma cells (RCCs). Materials and Methods: Cytotoxic activity was measured by MTT assay. Apoptosis was probed using the PI/annexin V method. Real-time PCR and western blot were used to test the levels of mRNA and protein, respectively. Luciferase assay was used to investigate whether CHOP regulated the expression of death receptor (DR) 5 through transcription. A xenogeneic tumor transplantation model was used to evaluate the anticancer effects of alternol/TRAIL in vivo. Results: When the mechanisms were investigated, we discovered that alternol increased DR5 expression. DR5 knockdown by siRNA eliminated the enhanced effect of alternol on TRAIL-mediated apoptosis. Alternol reduced the expression of antiapoptotic proteins and increased the levels of proapoptotic proteins. Moreover, alternol increased the level of CHOP, which is necessary for the enhancing effect of alternol on TRAIL-induced apoptosis, given that downregulation of CHOP abrogated the synergistic effect. DR5 upregulation induced by alternol required the production of reactive oxygen species (ROS). Removing ROS inhibited the induction of DR5 and blocked the antiapoptotic proteins induced by alternol. Conclusion: Taken together, our research suggested that alternol increased TRAIL-mediated apoptosis via inhibiting antiapoptotic proteins and upregulating DR5 levels via ROS generation and the CHOP pathway.
Highlights
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a member of the TNF super family
We examined whether alternol can potentiate TRAIL-induced apoptosis in human renal carcinoma cells (RCC) in vitro and in a tumor xenograft mouse model
We examined the effect of alternol on various RCCs
Summary
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a member of the TNF super family. TRAIL is a promising antitumor agent, given that it selectively induces apoptosis in tumor cells while sparing normal cells (Ashkenazi, 2015). Death receptor (DR) 4 (DR4, TRAIL-R1) and DR5 (TRAIL-R2) are Alternol Sensitizes TRAIL-Induced Apoptosis functional receptors. Other TRAIL receptors, such as decoy receptor-1 and -2 (DcR1 and DcR2) and osteoprotegerin (OPG), exhibit dominant negative effects through competing with DR4 and DR5 for TRAIL binding (Mahalingam et al, 2009). After binding to DR4 and/or DR5, TRAIL recruits Fasassociated death domain (FADD) and procaspase-8 into a deathinducing signaling complex (DISC) (Lemke et al, 2014). The autocatalytic processing of procaspase-8 into caspase-8 within the DISC leads to the subsequent downstream activation of the executioner caspase-3
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