Downregulation of X-linked inhibitor of apoptosis protein by ‘7-Benzylidenenaltrexone maleate’ sensitizes pancreatic cancer cells to TRAIL-induced apoptosis
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So Young Kim1, Sojung Park1, SeonA Yoo1, Jin Kyung Rho1,2, Eun Sung Jun3, Suhwan Chang3, Kyung Kon Kim1,2, Song Cheol Kim4 and Inki Kim1,2
1ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, 05505 South Korea
2Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, 05505, South Korea
3Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, 05505, South Korea
4Division of HBP Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, South Korea
Song Cheol Kim, email: email@example.com
Inki Kim, email: firstname.lastname@example.org
Keywords: BNTX, TRAIL, XIAP, PKCα, pancreatic cancer cells
Received: January 17, 2017 Accepted: April 14, 2017 Published: May 12, 2017
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 found that TRAIL-induced apoptosis was augmented by siRNA-mediated knockdown of XIAP. 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 growth of pancreatic tumor xenograft of animal model. 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.
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