Targeting a Novel Androgen Receptor-Repressed Pathway in Prostate Cancer Therapy
Technical Report,01 Sep 2016,31 Aug 2017
University of Pittsburgh Pittsburgh United States
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The primary goal of this study is to investigate the potential roles of protein kinase D PKD in mediating therapeutic resistance to ADT and to investigate the impact of PKD small molecule inhibitor SMI-based combination therapies to curtail ADT-induced therapy resistance. During the past funding cycle, we examined the cross-regulation of PKD1 by androgen signaling in prostate cancer cells. Our data has identified PKD1 as a novel androgen-repressed gene at transcriptional level. Kinetic analysis indicated that the repression of PKD1 by androgen required the induction of a repressor protein, and AR was required for the suppression of PKD1 by androgen. Downstream of AR, we identified fibroblast growth factor receptor substrate 2 FRS2 and its downstream MEKERK pathway as the mediators of androgen-induced PKD1 repression. Our study indicates that PKD1 is a novel androgen suppressed gene and can be downregulated by androgen through a novel ARFRS2MEKERK pathway.The upregulation of the prosurvival PKD1 by antiandrogens may contribute to therapeutic resistance in prostate cancer treatment.
- Medicine and Medical Research