Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-Resistant Prostate Cancer
Technical Report,15 Sep 2013,14 Sep 2017
Baylor College of Medicine Houston United States
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We previously demonstrated that stromal TGF-beta signaling induced the expression of several AR targets as well as MAPK4 in PCa LNCaP cells, and that MAPK4 induced ligand-independent AR activation in PCa cells. Therefore, we proposed to use in vitro PCastroma co-culture models and in vivo xenograft models to test our hypothesis on stromal TGF-beta signaling inducing MAPK4 for androgen-independent AR activation in PCa as a direct mechanism for CRPC relapse. Here, we have further demonstrated that MAPK4 strongly induces AR and GATA2 expression, as well as androgen-independent and -dependent activation of AR in PCa. We also demonstrated that knockdown of MAPK4 greatly inhibited AR activation in the TGF-beta treated LNCaPHPS19I co-cultures, indicating MAPK4 as a key mediator for stromal TGF-beta signaling induced AR activation in PCa cells. Furthermore, we demonstrated that MAPK4 promotes LNCaP xenograft growth in vivo in both intact and castrated SCID mice. Some technical difficulties has limited our ability to finish some xenograft and human tissue studies. Altogether, our data supports our hypothesis on stromal TGF-beta signaling inducing MAPK4 for PCa AR activation.
- Medicine and Medical Research