Molecular Pharmacological Approach Reveals Potential New Strategies to Suppress Androgen Receptor Signaling in Prostate Cancer

Androgen receptor (AR) plays a pivotal role in growth and survival of prostate cancer cells. Currently, androgen deprivation therapy is a standard approach to manage advanced and metastatic prostate cancer. In most patients, however, relapse eventually occurs and so far, only few treatment options are available to manage recurrence. Previous studies have demonstrated that, in hormone-refractory prostate cancer (HRPC), various mechanisms affect AR including overexpresssion, mutations and alternative splicing. These alterations can lead to androgen-independent AR activation or resistance to antiandrogen-mediated AR inhibition. In many cases, HRPC growth is still dependent on AR and therefore, AR inhibition by alternative methods would be a rational strategy to treat HRPC. Our recent work indicated that simultaneous inhibition of multiple forms of AR via small interfering RNA (siRNA)-mediated knockdown or by treatment with nigericin, an antibiotic derived from Streptomyces hygroscopicus, resulted in efficient growth suppression of HRPC. These data indicated that the inhibition of AR expression at the mRNA level could be an effective strategy to block a wide range of AR mutants or variants that are expressed in HRPC. Our chemical screening additionally identified new inhibitors of the AR-mediated signaling, such as SU1498 that is an inhibitor of vascular endothelial growth factor receptor 2 and 5-azacytidine that inhibits DNA methyltransferase. Collectively, these results provide novel potential strategies to suppress androgen receptor signaling in prostate cancer cells.