Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation
Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation
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DOI：
10.1073/pnas.0700420104
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发表时间：
2007-05-15
影响因子：
11.1
通讯作者：
Whang, Young E.
中科院分区：
文献类型：
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作者：
Mahajan, Nupam P.;Liu, Yuanbo;Whang, Young E.
雄激素受体（AR）的激活可能在前列腺癌的雄激素非依赖性进展中发挥作用。已经假定了AR激活的多种机制，包括酪氨酸激酶的刺激。我们和其他研究人员最近发现，活化的Cdc 42相关酪氨酸激酶Ack 1参与了晚期前列腺癌。在这里，我们提供了Ack 1和AR在前列腺癌细胞中相互作用的分子基础。活化的Ack 1促进LNCaP和LAPC-4前列腺异种移植肿瘤的雄激素非依赖性生长，AR募集到雄激素应答增强子，以及在雄激素不存在的情况下雄激素诱导的基因表达。调蛋白刺激的HER 2活化诱导Ack 1活化和AR酪氨酸磷酸化。Ack 1敲低抑制调蛋白依赖性AR酪氨酸磷酸化、AR报告活性、雄激素刺激的基因表达和AR募集。在雄激素和heregulin刺激后，ack 1被招募到雄激素反应增强子中。在18例原发性雄激素非依赖性前列腺肿瘤样本中，有8例检测到酪氨酸磷酸化AR蛋白，并与酪氨酸磷酸化Ack 1的检测相关。在雄激素依赖性肿瘤或良性前列腺样本中也没有升高。激活的Ack 1在Tyr-267和Tyr-363处磷酸化AR蛋白，两者均位于反式激活结构域内。Tyr-267突变完全消除，Tyr-363突变减少Ack 1诱导的AR报告基因激活和AR向雄激素应答增强子的募集。AR点突变体的表达抑制Ack 1驱动的异种移植肿瘤生长。因此，Ack 1被表面信号或致癌机制激活可能直接增强AR转录功能，并促进前列腺癌的雄激素非依赖性进展。靶向Ack 1激酶可能是前列腺癌的潜在治疗策略。
Activation of the androgen receptor (AR) may play a role in androgen-independent progression of prostate cancer. Multiple mechanisms of AR activation, including stimulation by tyrosine kinases, have been postulated. We and others have recently shown involvement of activated Cdc42-associated tyrosine kinase Ack1 in advanced human prostate cancer. Here we provide the molecular basis for interplay between Ack1 and AR in prostate cancer cells. Activated Ack1 promoted androgen-independent growth of LNCaP and LAPC-4 prostate xenograft tumors, AR recruitment to the androgen-responsive enhancer, and androgen-inducible gene expression in the absence of androgen. Heregulin-stimulated HER2 activation induced Ack1 activation and AR tyrosine phosphorylation. Ack1 knockdown inhibited heregulin-dependent AR tyrosine phosphorylation, AR reporter activity, androgen-stimulated gene expression, and AR recruitment. Ack1 was recruited to the androgen-responsive enhancers after androgen and heregulin stimulation. In 8 of 18 primary androgen-independent prostate tumor samples, tyrosine-phosphorylated AR protein was detected and correlated with the detection of tyrosine-phosphorylated Ack1. Neither was elevated in androgen-dependent tumors or benign prostate samples. Activated Ack1 phosphorylated AR protein at Tyr-267 and Tyr-363, both located within the transactivation domain. Mutation of Tyr-267 completely abrogated and mutation of Tyr-363 reduced Ack1-induced AR reporter activation and recruitment of AR to the androgen-responsive enhancer. Expression of AR point mutants inhibited Ack1-driven xenograft tumor growth. Thus, Ack1 activated by surface signals or oncogenic mechanisms may directly enhance AR transcriptional function and promote androgen-independent progression of prostate cancer. Targeting the Ack1 kinase may be a potential therapeutic strategy in prostate cancer.