TY - JOUR
T1 - Differential effects of prostate cancer therapeutics on neuroendocrine transdifferentiation
AU - Frigo, Daniel E.
AU - McDonnell, Donald P.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2008/3/1
Y1 - 2008/3/1
N2 - 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 downregulating 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.
AB - 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 downregulating 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.
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U2 - 10.1158/1535-7163.MCT-07-0480
DO - 10.1158/1535-7163.MCT-07-0480
M3 - Article
C2 - 18347151
AN - SCOPUS:41649097549
SN - 1535-7163
VL - 7
SP - 659
EP - 669
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 3
ER -