Accession Number : AD1047897


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


Descriptive Note : Technical Report,15 Sep 2013,14 Sep 2017


Corporate Author : Baylor College of Medicine Houston United States


Personal Author(s) : Yang, Feng


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1047897.pdf


Report Date : 01 Dec 2017


Pagination or Media Count : 35


Abstract : 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 PCa/stroma 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 LNCaP/HPS19I 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.


Descriptors :   prostate cancer , therapeutics , neoplasms , cells(biology , ligands , in vitro analysis , in vivo analysis , ANDROGENS , gene expression , METASTASIS


Subject Categories : Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE