Compensatory upregulation of tyrosine kinase Etk/BMX in response to androgen deprivation promotes castration-resistant growth of prostate cancer cells.
Compensatory upregulation of tyrosine kinase Etk/BMX in response to androgen deprivation promotes castration-resistant growth of prostate cancer cells.
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DOI：
10.1158/0008-5472.can-09-4610
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发表时间：
2010-07-01
期刊：
影响因子：
11.2
通讯作者：
Qiu Y
中科院分区：
文献类型：
--
作者：
Dai B;Chen H;Guo S;Yang X;Linn DE;Sun F;Li W;Guo Z;Xu K;Kim O;Kong X;Melamed J;Qiu S;Chen H;Qiu Y
我们之前表明，非受体酪氨酸激酶 Etk/BMX 在小鼠前列腺中的靶向表达会诱导前列腺上皮内瘤变，这意味着 Etk 在前列腺癌的发生和进展中可能具有因果作用。在此，我们报告 Etk 在人类和小鼠前列腺中因雄激素消融而上调。 Etk 表达似乎受到雄激素和 IL-6 的差异调节，这可能是由前列腺癌细胞中的雄激素受体 (AR) 介导的。我们对包含 112 个人类前列腺肿瘤样本的组织微阵列进行的免疫组织化学分析表明，Etk 表达在激素难治性前列腺癌中升高，并且与 AR 的酪氨酸磷酸化呈正相关（Pearson 相关系数 ρ=0.71，p<0.0001）。 AR 酪氨酸磷酸化在 Etk 过表达细胞中增加，表明 Etk 可能是除 Src 和 Ack-1 之外的另一种酪氨酸激酶，可磷酸化 AR。我们还证明，Etk 可以通过其 SH2 结构域直接与 AR 相互作用，这种相互作用可能会阻止 AR 与 Mdm2 的结合，从而导致 AR 在雄激素耗尽的条件下稳定。雄激素敏感的 LNCaP 细胞中 Etk 的过度表达可促进肿瘤生长，而通过特定的 shRNA 敲低激素不敏感的前列腺癌细胞中的 Etk 表达可在雄激素耗尽的条件下抑制肿瘤生长。综上所述，我们的数据表明，Etk 可能是前列腺雄激素消融激活的适应性代偿机制的一个组成部分，并且可能至少部分通过直接调节 AR 信号通路在激素抵抗中发挥作用。
We previously showed that targeted expression of non-receptor tyrosine kinase Etk/BMX in mouse prostate induces prostate intraepithelial neoplasia, implying a possible causal role of Etk in prostate cancer development and progression. Here, we report that Etk is upregulated in both human and mouse prostates in response to androgen ablation. Etk expression appears to be differentially regulated by androgen and IL-6, which is possibly mediated by the androgen receptor (AR) in prostate cancer cells. Our immunohistochemical analysis of tissue microarrays containing 112 human prostate tumor samples revealed that Etk expression is elevated in hormone refractory prostate cancer and positively correlated with tyrosine phosphorylation of AR (Pearson correlation coefficient ρ=0.71, p<0.0001). AR tyrosine phosphorylation is increased in Etk overexpressing cells, suggesting that Etk may be another tyrosine kinase, in addition to Src and Ack-1, which can phosphorylate AR. We also demonstrated that Etk can directly interact with AR via its SH2 domain and such interaction may prevent the association of AR with Mdm2, leading to stabilization of AR under androgen-depleted conditions. Overexpression of Etk in androgen-sensitive LNCaP cells promotes tumor growth while knocking-down Etk expression in hormone-insensitive prostate cancer cells by a specific shRNA inhibits tumor growth under androgen-depleted conditions. Taken together, our data suggest that Etk may be a component of the adaptive compensatory mechanism activated by androgen ablation in prostate and may play a role in hormone resistance, at least in part, through direct modulation of AR signaling pathway.