Research Papers:

Downregulation of X-linked inhibitor of apoptosis protein by ‘7-Benzylidenenaltrexone maleate’ sensitizes pancreatic cancer cells to TRAIL-induced apoptosis

So Young Kim, Sojung Park, SeonA Yoo, Jin Kyung Rho, Eun Sung Jun, Suhwan Chang, Kyung Kon Kim, Song Cheol Kim _ and Inki Kim

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Oncotarget. 2017; 8:61057-61071. https://doi.org/10.18632/oncotarget.17841

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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

Correspondence to:

Song Cheol Kim, email: [email protected]

Inki Kim, email: [email protected]

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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