PT  - JOURNAL ARTICLE
AU  - Elena V Fernandez
AU  - Kelie M. Reece
AU  - Ariel M. Ley
AU  - Sarah M. Troutman
AU  - Tristan Sissung
AU  - Douglas K. Price
AU  - Cindy H. Chau
AU  - William Figg
TI  - Dual Targeting of the Androgen Receptor and Hypoxia-inducible Factor 1α Pathways Synergistically Inhibits Castration-Resistant Prostate Cancer Cells
AID  - 10.1124/mol.114.097477
DP  - 2015 Jan 01
TA  - Molecular Pharmacology
PG  - mol.114.097477
4099  - http://molpharm.aspetjournals.org/content/early/2015/03/31/mol.114.097477.short
4100  - http://molpharm.aspetjournals.org/content/early/2015/03/31/mol.114.097477.full
AB  - Background: Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). While enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Given that both AR and hypoxia inducible factor 1-alpha (HIF-1α) are key regulators of these processes, dual targeting of both signaling axis represents an attractive therapeutic approach. Methods: Crosstalk of the AR and HIF-1α signaling pathways were examined in prostate cancer cell lines (LNCaP, 22Rv1) with assays measuring the effect of androgen and hypoxia on AR-dependent and hypoxia-inducible gene transcription, protein expression, cell proliferation, and apoptosis. HIF-1α inhibition was achieved by siRNA silencing HIF-1α or via chetomin, a disruptor of HIF-1α-p300 interactions. Results: In prostate cancer cells, the gene expression of AR targets (KLK3, FKBP5, TMPRSS2) was repressed by HIF-signaling; conversely, specific HIF-1α target expression was induced by DHT-mediated AR signaling. Treatment of CRPC cells with enzalutamide or HIF-1α inhibition attenuated AR-regulated and HIF-1α-mediated gene transcription. The combination of enzalutamide and HIF-1α inhibition was more effective than either treatment alone. Similarly, the combination also reduced VEGF protein levels. HIF-1α siRNA synergistically enhanced the inhibitory effect of enzalutamide on cell growth in LNCaP and enzalutamide-resistant 22Rv1 cells via increased enzalutamide-induced apoptosis. Conclusions: The combination of enzalutamide with HIF-1α inhibition resulted in synergistic inhibition of AR-dependent and gene-specific HIF-dependent expression and prostate cancer cell growth.