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, Seon A. Yoo, Jin Kyung Rho, Eun Sung Jun, Suhwan Chang, Kyung Kon Kim, Song Cheol Kim, Inki Kim

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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 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.

Original languageEnglish
Pages (from-to)61057-61071
Number of pages15
JournalOncotarget
Volume8
Issue number37
DOIs
StatePublished - 1 Sep 2017

Keywords

  • BNTX
  • PKCα
  • Pancreatic cancer cells
  • TRAIL
  • XIAP

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