HIF-2α dictates the susceptibility of pancreatic cancer cells to TRAIL by regulating survivin expression

// Nanae Harashima 1 , Keizo Takenaga 2 , Miho Akimoto 2 and Mamoru Harada 1 1 Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan 2 Department of Life Science, Shimane University Faculty of Medicine, Shimane, Japan Correspondence to: Mamoru Harada, email: haramamo@med.shimane-u.ac.jp Keywords: hypoxia, HIF-2α, TRAIL, surviving, pancreatic cancer Received: September 07, 2016      Accepted: March 20, 2017      Published: April 17, 2017 ABSTRACT Cancer cells develop resistance to therapy by adapting to hypoxic microenvironments, and hypoxia-inducible factors (HIFs) play crucial roles in this process. We investigated the roles of HIF-1α and HIF-2α in cancer cell death induced by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) using human pancreatic cancer cell lines. siRNA-mediated knockdown of HIF-2α, but not HIF-1α, increased susceptibility of two pancreatic cancer cell lines, Panc-1 and AsPC-1, to TRAIL in vitro under normoxic and hypoxic conditions. The enhanced sensitivity to TRAIL was also observed in vivo . This in vitro increased TRAIL sensitivity was observed in other three pancreatic cancer cell lines. An array assay of apoptosis-related proteins showed that knockdown of HIF-2α decreased survivin expression. Additionally, survivin promoter activity was decreased in HIF-2α knockdown Panc-1 cells and HIF-2α bound to the hypoxia-responsive element in the survivin promoter region. Conversely, forced expression of the survivin gene in HIF-2α shRNA-expressing Panc-1 cells increased resistance to TRAIL. In a xenograft mouse model, the survivin suppressant YM155 sensitized Panc-1 cells to TRAIL. Collectively, our results indicate that HIF-2α dictates the susceptibility of human pancreatic cancer cell lines, Panc-1 and AsPC-1, to TRAIL by regulating survivin expression transcriptionally, and that survivin could be a promising target to augment the therapeutic efficacy of death receptor-targeting anti-cancer therapy.