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BMC Cancer. 2012; 12: 293.
Published online Jul 17, 2012. doi:  10.1186/1471-2407-12-293
PMCID: PMC3466155
Prolyl hydroxylase 2 dependent and Von-Hippel-Lindau independent degradation of Hypoxia-inducible factor 1 and 2 alpha by selenium in clear cell renal cell carcinoma leads to tumor growth inhibition
Sreenivasulu Chintala,corresponding author1,3 Tanbir Najrana,1 Karoly Toth,1 Shousong Cao,1,2 Farukh A Durrani,1 Roberto Pili,2 and Youcef M Rustum1
1Department of Cancer Biology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA
2Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, 14263, USA
3Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA
corresponding authorCorresponding author.
Sreenivasulu Chintala: sreenivasulu.chintala/at/roswellpark.org; Tanbir Najrana: tanbir.najrana/at/roswellpark.org; Karoly Toth: karoly.toth/at/roswellpark.org; Shousong Cao: shousong.cao/at/roswellpark.org; Farukh A Durrani: farukh.durrani/at/roswellpark.org; Roberto Pili: roberto.pili/at/roswellpark.org; Youcef M Rustum: youcef.rustum/at/roswellpark.org
Received November 28, 2011; Accepted June 27, 2012.
Abstract
Background
Clear cell renal cell carcinoma (ccRCC) accounts for more than 80% of the cases of renal cell carcinoma. In ccRCC deactivation of Von-Hippel-Lindau (VHL) gene contributes to the constitutive expression of hypoxia inducible factors 1 and 2 alpha (HIF-α), transcriptional regulators of several genes involved in tumor angiogenesis, glycolysis and drug resistance. We have demonstrated inhibition of HIF-1α by Se-Methylselenocysteine (MSC) via stabilization of prolyl hydroxylases 2 and 3 (PHDs) and a significant therapeutic synergy when combined with chemotherapy. This study was initiated to investigate the expression of PHDs, HIF-α, and VEGF-A in selected solid cancers, the mechanism of HIF-α inhibition by MSC, and to document antitumor activity of MSC against human ccRCC xenografts.
Methods
Tissue microarrays of primary human cancer specimens (ccRCC, head & neck and colon) were utilized to determine the incidence of PHD2/3, HIF-α, and VEGF-A by immunohistochemical methods. To investigate the mechanism(s) of HIF-α inhibition by MSC, VHL mutated ccRCC cells RC2 (HIF-1α positive), 786–0 (HIF-2α positive) and VHL wild type head & neck cancer cells FaDu (HIF-1α) were utilized. PHD2 and VHL gene specific siRNA knockdown and inhibitors of PHD2 and proteasome were used to determine their role in the degradation of HIF-1α by MSC.
Results
We have demonstrated that ccRCC cells express low incidence of PHD2 (32%), undetectable PHD3, high incidence of HIF-α (92%), and low incidence of VEGF-A compared to head & neck and colon cancers. This laboratory was the first to identify MSC as a highly effective inhibitor of constitutively expressed HIF-α in ccRCC tumors. MSC did not inhibit HIF-1α protein synthesis, but facilitated its degradation. The use of gene knockdown and specific inhibitors confirmed that the inhibition of HIF-1α was PHD2 and proteasome dependent and VHL independent. The effects of MSC treatment on HIF-α were associated with significant antitumor activity against ccRCC xenograft.
Conclusions
Our results show the role of PHD2/3 in stable expression of HIF-α in human ccRCC. Furthermore, HIF-1α degradation by MSC is achieved through PHD2 dependent and VHL independent pathway which is unique for HIF-α regulation. These data provide the basis for combining MSC with currently used agents for ccRCC.
Keywords: Prolyl hydroxylases, Hypoxia-inducible factor, Clear cell renal cell carcinoma, Selenium
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