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

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.

Gene Differential Expression and Interaction Networks Illustrate the Biomarkers and Molecular Mechanisms of Atherosclerotic Cerebral Infarction

“…However, it was also found that both GSE16561 and GSE100927 were enriched in MAPK, Cytokine-cytokine receptor interaction, antigen processing and presentation, and cGMP-PKG signaling pathways. MAPK pathway is implicated in various cellular activities including cell apoptosis and inflammation [ 23 , 24 ]. Abnormally activated MAPK pathways serve as a major role in the development of multiple inflammations, and targeting MAPK pathways have been proved to effectively alleviate the symptom of atherosclerosis [ 25 ].…”

Unravelling the Role of Kinases That Underpin Androgen Signalling in Prostate Cancer

“…IL-6 can also activate p38 MAPK signalling independent of androgen, which by this mechanism would increase AR signalling [87]. Inhibition of p38 MAPK signalling decreased proliferation in AR-positive cell lines in normoxia, and growth was further compromised by hypoxia, which is another trigger for p38 MAPK activation [88].…”

“…During ADT, the genomic repression of the p38 MAPK pathway would be ablated and reversed. One of the results would be increased hsp27, which would be predicted to increase stability and nuclear translocation of the AR [87,88], as well as enhance survival via the p38 MAPK pathway [88]. Activation of the p38 MAPK pathway has also been linked to epithelial-mesenchymal transition (EMT) and metastasis [88,168].…”

“…One of the results would be increased hsp27, which would be predicted to increase stability and nuclear translocation of the AR [87,88], as well as enhance survival via the p38 MAPK pathway [88]. Activation of the p38 MAPK pathway has also been linked to epithelial-mesenchymal transition (EMT) and metastasis [88,168]. By identifying MAP2K3 and MAP2K6 repression by the AR, continuing to repress these alongside ADT could reduce androgen independence caused by the increase in the p38 MAPK pathway.…”

The Hypoxia–Long Noncoding RNA Interaction in Solid Cancers

“…In addition, the in vivo growth of ovarian cancer cells is hampered by CDKN2B-AS1 depletion [ 138 ] ( Figure 2 and Table 2 ). Hypoxia is known to activate p38, thus leading to cancer aggressiveness via enhancing cell survival [ 139 , 140 ]. Moreover, HIF-1α is activated by p38 [ 139 ].…”