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.
Highlights
Hypoxia is an important condition for solid tumors to progress and metastasize
We investigated the roles of hypoxia-inducible factors (HIFs)-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 AsPC1, to TNFrelated apoptosis-inducing ligand (TRAIL) in vitro under normoxic and hypoxic conditions
We found for the first time that HIF-2α dictates the susceptibility of pancreatic cancer cell lines, Panc-1 and AsPC-1, to TRAIL, by transcriptionally regulating survivin, an anti-apoptotic molecule, and that survivin may be a promising target to augment the therapeutic efficacy of death receptors (DRs)-targeting anti-cancer therapy
Summary
Hypoxia is an important condition for solid tumors to progress and metastasize. The concentration of oxygen in normal tissues is approximately 5%, whereas in solid tumors is usually below 1% [1]. HIF-α proteins are degraded through the ubiquitin-proteasome pathway [3], whereas the HIF-α and β-subunit complexes accumulate under hypoxic conditions. These complexes translocate to the nucleus and bind to hypoxia-responsive elements (HREs) in the promoter regions of targeted genes. HIFs are inducible in normal cells [4, 5], their expressions are frequently higher in various types of cancers [6]. HIFs play critical roles in cancer cells resistant to therapy [8, 9]. The roles of HIF-2α in cancers resistant to therapy have not been fully investigated
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