Frigo Daniel E, McDonnell Donald P
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Mol Cancer Ther. 2008 Mar;7(3):659-69. doi: 10.1158/1535-7163.MCT-07-0480.
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.
雄激素剥夺疗法被广泛用于治疗晚期前列腺癌。然而，这种干预策略的有效性通常是短暂的，因为疾病最终会发展为激素难治性状态。近年来，已经明确即使在抗雄激素耐药的癌症中，雄激素受体（AR）信号轴仍然完整，并且是前列腺癌生长所必需的。因此，人们对开发部分通过下调肿瘤中AR表达起作用的小分子越来越感兴趣。矛盾的是，AR表达已被证明在防止上皮性前列腺癌细胞向与肿瘤进展相关的神经内分泌表型转分化方面很重要。因此，我们在已建立的前列腺癌细胞模型中评估了部分通过降低AR水平起作用的前列腺癌治疗药物对神经内分泌分化的相对影响。这些研究表明，虽然组蛋白去乙酰化酶抑制剂可以下调AR表达，但它们会增加神经内分泌标志物的表达并改变细胞形态。使用经典AR拮抗剂或小干扰RNA介导的AR消融抑制AR信号传导会诱导不完全的神经内分泌分化。重要的是，热休克蛋白90（Hsp90）抑制剂格尔德霉素有效地下调AR表达，而对神经内分泌分化没有影响。综上所述，这些数据表明，临床上用于预防前列腺癌进展的药物的表型反应并不相同，这一发现具有重要的治疗意义。
