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Clinical Cancer Research Vol. 9, 2416-2425, July 2003
© 2003 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

Androgens Stimulate Hypoxia-inducible Factor 1 Activation via Autocrine Loop of Tyrosine Kinase Receptor/Phosphatidylinositol 3'-Kinase/Protein Kinase B in Prostate Cancer Cells1

Nicola J. Mabjeesh, Margaret T. Willard, Carrie E. Frederickson, Hua Zhong and Jonathan W. Simons2

Winship Cancer Institute, Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, Georgia 30322

Purpose: Androgen deprivation is implicated in reducing neoangiogenesis in prostate cancer (PCA). Androgens regulate the expression of the vascular endothelial growth factor (VEGF); hypoxia stimulates VEGF expression through the activation of the transcriptional factor, hypoxia-inducible factor 1 (HIF-1). We tested the hypothesis that an effect of androgens on VEGF expression is regulated directly by HIF-1 and HIF-2, and antiandrogens block HIF function.

Experimental Design: Androgen and antiandrogen effects were evaluated on HIF-1{alpha} protein and HIF-1 transcriptional activation in human PCA cells.

Results: Dihydrotestosterone (DHT) activates HIF-1{alpha} nuclear protein expression in LNCaP cells but not in androgen receptor-negative PC-3 cells. HIF-1{alpha} expression is correlated with the transactivation of a hypoxia-responsive element-driven reporter gene and with the production of VEGF protein. The effect of DHT on HIF-1 was blocked by nonsteroidal antiandrogens, flutamide and bicalutamide. DHT does not affect HIF-1{alpha} mRNA levels but regulates HIF-1{alpha} protein expression through a translation-dependent pathway. PC-3 cells when incubated with increasing amounts of conditioned medium from LNCaP cells treated with DHT experienced a dose-dependent increase in HIF-1{alpha}. This induction was not seen either when LNCaP cells were treated with flutamide or conditioned medium were pretreated with antibody to the epidermal growth factor (EGF). HIF-1 activation by DHT was blocked by LY294002, a potent inhibitor of the phosphatidylinositol 3'-kinase signaling pathway, whereas HIF-1 activation by EGF, as ligand, was not inhibited by flutamide. In contrast, HIF-2{alpha} protein was not affected by androgens or antiandrogens.

Conclusion: Androgens activate HIF-1, driving VEGF expression in androgen-sensitive LNCaP cells. This regulation is mediated through an autocrine loop involving EGF/phosphatidylinositol 3'-kinase/protein kinase B, which in turn activate HIF-1{alpha} and HIF-1-regulated gene expression. Therapeutic actions of antiandrogens in PCA include inhibition of HIF-1 function.


Commentary

HIF-{alpha}, a Gender Independent Transcription Factor
Quynh-Thu Le and Amato J. Giaccia
Clin. Cancer Res. 2003 9: 2391-2393. [Full Text] [PDF]



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