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Carcinogenesis Advance Access published online on June 9, 2008
Carcinogenesis, doi:10.1093/carcin/bgn132
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Hypoxia-inducible Factor-2{alpha} Regulates The Expression of TRAIL Receptor DR5 in Renal Cancer Cells

S Mahajan1, VR Dammai1,2, T Hsu1,2 and AS Kraft1,#

1 Hollings Cancer Center, Charleston, SC, USA
2 Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA

# Reprint requests should be addressed to Andrew S. Kraft at 86 Jonathan Lucas Street, Charleston, SC 29425, USA, 843-792-8284, kraft{at}musc.edu

To understand the role of HIF-2{alpha} in regulating sensitivity of renal cancer cells to TRAIL- induced apoptosis, we transfected wild type and mutant VHL proteins into TRAIL-sensitive, VHL-negative A498 cells. We find that wild type VHL, but not the VHL mutants S65W and C162F that do not degrade HIF proteins, cause TRAIL resistance. Knock-down of the HIF-2{alpha} protein by RNA interference (shRNA) blocked TRAIL-induced apoptosis, decreased the level of TRAIL receptor (DR5) protein, and inhibited the transcription of DR5 mRNA. By using luciferase constructs containing the upstream region of the DR5 promoter, we demonstrate that HIF-2{alpha} stimulates the transcription of the DR5 gene by activating the upstream region between –448 and –1188. Because HIF-2{alpha} is thought to exert its effect on gene transcription by interacting with the Max protein partner of Myc in the Myc/Max dimer, siRNAs to Myc were used to lower the levels of this protein. In multiple renal cancer cell lines decreasing the levels of Myc blocked the ability of HIF-2{alpha} to stimulate DR5 transcription. PS-341 (VELCADE, bortezomib), a proteasome inhibitor used to treat human cancer, increases the levels of both HIF-2{alpha} and c-Myc and elevates the level of DR5 in renal cancer, sensitizing renal cancer cells to TRAIL therapy. Similarly, increasing HIF-2{alpha} in prostate and lung cancer cell lines increased the levels of DR5. Thus, in renal cancer cell lines expressing HIF-2{alpha}, this protein plays a role in regulating the levels of the TRAIL receptor DR5.

Key Words: renal cancer • HIF-2{alpha} • TRAIL • apoptosis • VHL

This work was supported by NIH R01 CA104710 (Kraft), P01CA78582 and R01 CA109860 (Hsu) and R01 CA128002 (Dammai).

Received November 28, 2007; revised March 19, 2008; accepted May 25, 2008.


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