Abstract
Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is a potential biological anticancer agent. However, a wide range of human primary cancers, including pancreatic cancer, display resistance to apoptosis induction by TRAIL. Therefore, this resistance needs to be overcome to allow TRAIL to be successfully used in cancer therapy. In this study, we performed a compound screen to isolate TRAIL sensitizers and found that one of the identified compounds, 7‐benzylidenenaltrexone maleate (BNTX), sensitized pancreatic cancer cells to TRAIL‐induced apoptotic cell death. The combination of BNTX with TRAIL promoted the release of cytochrome c from mitochondria into cytosol with caspase activation and a resulting increase in annexin‐V‐stained cells. From a mechanistic perspective, we found that BNTX downregulated X‐linked inhibitor of apoptosis protein (XIAP) expression when used in combination with TRAIL and BNTX and that TRAIL‐induced apoptosis was augmented by the siRNA‐mediated knockdown of XIAP with caspase activation. We further demonstrated that BNTX promoted the ubiquitin/proteasome‐dependent degradation of XIAP protein via protein kinase C (PKC) alpha/AKT pathway inhibition. Moreover, combined treatment by BNTX with TRAIL suppressed tumor growth in vivo. Therefore, we suggest that inhibitor of apoptosis protein‐mediated resistance of pancreatic cancer cells to anticancer therapeutics can be overcome by inhibiting the PKCα/AKT pathway.Support or Funding InformationThis work was supported (40%) by (1) the Basic Science Research Program (NRF‐2016R1D1A1B03932365) funded by the Ministry of Science, Information & Communication Technology (ICT) and Future Planning, and (2) supported (30%) by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (Grant Number: HI14C2640), and (3) supported by a Center for Women in Science, Engineering and Technology (WISET) grant (20%) funded by the Ministry of Science, ICT & Future Planning of Korea (MSIP) under the Program for Returners into R&D (KW‐2015‐PPD‐0134), and (4) supported by internal research program of ASAN Institute for Life Sciences (10%) (16‐512 & 16‐586).
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