Small Molecule Inhibitors of Androgen Receptor Action in Prostate Cancer Cells
SMALL MOLECULE INHIBITORS OF ANDROGEN RECEPTOR ACTION IN PROSTATE CANCER CELLS
Coinvestigator: Elizabeth Wilson (Univ North Carolina)
Alumni: Dr. Milu Cherian, Khin-Khin Soe Wu
Androgens, acting through the androgen receptor (AR), play a key role in the development and progression of prostate cancer. While antiandrogen and androgen deprivation therapy are standard therapies for metastatic and recurrent prostate cancer, most patients develop resistance. Because of the continued role of AR in the growth of recurrent prostate cancer, the AR remains an important therapeutic target. To identify novel inhibitors of AR transactivation that block growth of prostate cancer cells, a luciferase-based high throughput screen of ~160,000 small molecules was performed in cells stably expressing AR and a prostate-specific antigen (PSA)-luciferase reporter. CPIC (1-(3-(2-chlorophenoxy) propyl)-1H-indole-3-carbonitrile) was identified as a small molecule that blocks AR transactivation to a greater extent than other steroid receptors. CPIC inhibited AR-mediated proliferation of androgen-sensitive prostate cancer cell lines, with minimal toxicity in AR-negative cell lines. CPIC treatment also reduced the anchorage-independent growth of LAPC-4 prostate cancer cells. CPIC functioned as a pure antagonist by inhibiting the expression of AR-regulated genes in LAPC-4 cells that express wild-type AR, and exhibited weak agonist activity in LNCaP cells that express the mutant AR-T877A. CPIC treatment did not reduce AR levels or alter its nuclear localization. We used chromatin immunoprecipitation to identify the site of action of CPIC. CPIC inhibited recruitment of androgen-bound AR to the PSA promoter and enhancer sites to a greater extent than bicalutamide. CPIC is a new therapeutic inhibitor that targets AR-mediated gene activation with potential to arrest the growth of prostate cancer.
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