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Novel Therapeutic Targets to Inhibit Tumor Microenvironment-Induced Castration Resistant Prostate Cancer

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Technical Report,15 Sep 2015,14 Sep 2016

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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 inducingMAPK4 for androgen-independent AR activation in PCa as a direct mechanism for CRPC relapse. In this third year, we solved some previously encountered technical problems and successfully established an LNCaP cell line with Dox-inducible overexpression of MAPK4, and used it to demonstrate 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 ofMAPK4 greatly inhibited AR activation in the LNCaPHPS19I co-cultures, supporting a crucial role of MAPK4 in AR activation in these co-cultures. We are exploring several avenues to solve other technical problems, which have caused some significant delays. We expect to be able to fully finish Aim 1 and partially finish Aims 2 and 3 at the conclusion of this award.

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  • Medicine and Medical Research

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