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Carcinogenesis Advance Access originally published online on June 9, 2008
Carcinogenesis 2008 29(9):1734-1741; doi:10.1093/carcin/bgn132
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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Hypoxia-inducible factor-2{alpha} regulates the expression of TRAIL receptor DR5 in renal cancer cells

S. Mahajan1, V. Dammai1,2, T. Hsu1,2 and A.S. Kraft1,*

1 Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA
2 Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA

* To whom correspondence should be addressed. Tel: +1 843 792 8284; Fax: +1 843 792 9456; Email: kraft{at}musc.edu

To understand the role of hypoxia-inducible factor (HIF)-2{alpha} in regulating sensitivity of renal cancer cells to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis, we transfected wild-type and mutant von Hippel Lindau (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 (short hairpin RNA) blocked TRAIL-induced apoptosis, decreased the level of TRAIL receptor (DR5) protein and inhibited the transcription of DR5 messenger RNA. 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, small interfering RNAs 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.

Abbreviations: cDNA, complementary DNA; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GFP, green fluorescent protein; HIF, hypoxia-inducible factor; mRNA, messenger RNA; PCR, polymerase chain reaction; RCC, renal cell carcinoma; shRNA, short hairpin RNA; siRNA, small interfering RNA; TRAIL, tumor necrosis factor-related apoptosis inducing ligand; VHL, von Hippel Lindau

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


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