p38 MAPK Inhibition Mitigates Hypoxia-Induced AR Signaling in Castration-Resistant Prostate Cancer

SIMPLE SUMMARY: Progression of prostate cancer to a castration-resistant state is associated with poor patient outcomes, and new therapeutic targeting approaches are needed. Poorly oxygenated (hypoxic) cancer cells are resistant to many treatment modalities, and it is therefore important that novel therapies also target these cells. Here we show that targeting the p38 MAPK protein kinase can inhibit growth and survival of both well-oxygenated and hypoxic castration resistant prostate cancer cells and prolong survival of tumor bearing mice. p38 MAPK targeting inhibited phosphorylation of the chaperone protein Hsp27 and activity of the androgen receptor. This demonstrates that prostate cancer cells can remain dependent on the p38 MAPK/Hsp27 signaling axis upon progression to castration-resistance, and that hypoxia does not offer protection against targeting this pathway. ABSTRACT: Background: Aberrant androgen receptor (AR) signaling is a major driver of castration-resistant prostate cancer (CRPC). Tumor hypoxia increases AR signaling and is associated with treatment resistance in prostate cancer. Heat shock protein 27 (Hsp27) is a molecular chaperone that is activated in response to heat shock and hypoxia. Hsp27 has previously been reported to facilitate AR nuclear translocation in a p38 mitogen-activated protein kinase (MAPK) dependent manner in castration-sensitive prostate cancer cell lines. Here, we evaluated the potential for inhibiting p38 MAPK/Hsp27 mediated AR signaling under normoxia and hypoxia in experimental models of CRPC. Methods: We inhibited p38 MAPK with SB203580 in prostate cancer cell lines and measured Hsp27 phosphorylation, AR activity, cell proliferation, and clonogenicity under normoxia and hypoxia. AR activity was measured using an androgen response element driven reporter assay and qPCR to measure expression of AR target genes. Xenograft-bearing mice were treated with SB203580 to measure tumor growth and serum prostate specific antigen (PSA). Results: Our results indicate that p38 MAPK and Hsp27 are activated under normoxia and hypoxia in response to androgens in CRPC cells. p38 MAPK inhibition diminished Hsp27 activation and the hypoxia-mediated increase in AR activity. Additionally, inhibition of p38 MAPK activity decreased proliferation and survival of CRPC cells in vitro and prolonged the survival of tumor-bearing mice. Conclusions: These results suggest that p38 MAPK inhibition may represent a therapeutic strategy to disrupt AR signaling in the heterogeneous CRPC tumor microenvironment.