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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Combinatorial activities of Akt and B-Raf/Erk signaling in a mouse model of androgen-independent prostate cancer
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Combinatorial activities of Akt and B-Raf/Erk signaling in a mouse model of androgen-independent prostate cancer

机译：Akt和B-Raf / Erk信号在雄激素非依赖性前列腺癌小鼠模型中的组合活性

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摘要

Androgen independence is responsible for most prostate cancer lethality, yet currently there are no effective clinical treatments. We have been investigating the mechanisms underlying androgen-independent prostate cancer in Nkx3.1;Pten mutant mice, which display salient features of the disease, including a requirement for wild-type androgen receptor (AR) signaling. We now demonstrate that the Akt and Erk MAP kinase signaling pathways are activated in androgen-independent lesions of these mice. Forced activation of either Akt or Erk signaling in an androgen-responsive prostate cancer cell line promotes hormone-independent but AR-dependent growth in culture. Although these pathways act additively in culture, they act synergistically in vivo to promote tumorigenicity and androgen independence in the context of the prostate micro-environment. We propose that androgen independence emerges by means of epithelial-stromal competition, in which activation of Akt and Erk promotes AR activity in the prostate epithelium while counteracting antagonistic effects of the stroma.
机译：雄激素独立性是造成大多数前列腺癌致死率的原因，但目前尚无有效的临床治疗方法。我们一直在研究Nkx3.1; Pten突变小鼠中雄激素非依赖性前列腺癌的潜在机制，该机制显示出该疾病的显着特征，包括对野生型雄激素受体（AR）信号的需求。我们现在证明在这些小鼠的雄激素非依赖性病变中激活了Akt和Erk MAP激酶信号通路。雄激素反应性前列腺癌细胞系中Akt或Erk信号的强制激活促进了激素依赖性但AR依赖性培养的生长。尽管这些途径在培养中具有累加作用，但是它们在前列腺微环境的情况下在体内具有协同作用，以促进致瘤性和雄激素非依赖性。我们提出雄激素独立性通过上皮-间质竞争而出现，其中Akt和Erk的激活促进前列腺上皮中的AR活性，同时抵消基质的拮抗作用。

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