Differential effects of prostate cancer therapeutics on neuroendocrine transdifferentiation.

Published

Journal Article

Androgen ablation therapy is widely used for the treatment of advanced prostate cancer. However, the effectiveness of this intervention strategy is generally short-lived as the disease ultimately progresses to a hormone-refractory state. In recent years, it has become clear that even in antiandrogen-resistant cancers the androgen receptor (AR) signaling axis is intact and is required for prostate cancer growth. Thus, there is a heightened interest in developing small molecules that function in part by down-regulating AR expression in tumors. Paradoxically, AR expression has been shown to be important in preventing the transdifferentiation of epithelial prostate cancer cells toward a neuroendocrine phenotype associated with tumor progression. Consequently, we have evaluated the relative effect of prostate cancer therapeutics that function in part by depleting AR levels on neuroendocrine differentiation in established cellular models of prostate cancer. These studies reveal that although histone deacetylase inhibitors can down-regulate AR expression they increase the expression of neuroendocrine markers and alter cellular morphology. Inhibition of AR signaling using classic AR antagonists or small interfering RNA-mediated AR ablation induces incomplete neuroendocrine differentiation. Importantly, the Hsp90 inhibitor geldanamycin effectively down-regulates AR expression while having no effect on neuroendocrine differentiation. Taken together, these data show that the phenotypic responses to pharmacologic agents used in the clinic to prevent the progression of prostate cancer are not equivalent, a finding of significant therapeutic importance.

Full Text

Duke Authors

Cited Authors

  • Frigo, DE; McDonnell, DP

Published Date

  • March 2008

Published In

Volume / Issue

  • 7 / 3

Start / End Page

  • 659 - 669

PubMed ID

  • 18347151

Pubmed Central ID

  • 18347151

International Standard Serial Number (ISSN)

  • 1535-7163

Digital Object Identifier (DOI)

  • 10.1158/1535-7163.MCT-07-0480

Language

  • eng

Conference Location

  • United States