Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer.
Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer.
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DOI：
10.1016/j.ccr.2011.04.008
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发表时间：
2011-05-17
期刊：
影响因子：
50.3
通讯作者：
Sawyers CL
中科院分区：
文献类型：
--
作者：
Carver BS;Chapinski C;Wongvipat J;Hieronymus H;Chen Y;Chandarlapaty S;Arora VK;Le C;Koutcher J;Scher H;Scardino PT;Rosen N;Sawyers CL
前列腺癌的特征是其对雄激素受体的依赖性和PI3K信号的频繁激活。我们发现，AR转录输出减少，在人类和小鼠肿瘤与PTEN缺失和PI3K途径抑制激活AR信号通过解除反馈抑制HER激酶。类似地，AR抑制通过降低AKT磷酸酶PHLPP的水平来激活AKT信号传导。因此，这两种致癌途径通过相互反馈相互交叉调节。抑制其中一种会激活另一种，从而维持肿瘤细胞的存活。然而，PI3K和AR信号传导的组合药理学抑制在Pten缺陷的鼠前列腺癌模型和人前列腺癌异种移植物中引起几乎完全的前列腺癌消退，表明两种途径协调地支持存活。前列腺癌中两种最常激活的信号通路由AR和PI3K驱动。PI3K通路的抑制剂处于早期临床试验中，AR抑制剂在大多数患者中产生临床应答。然而，这些抑制剂很少在临床前模型中诱导肿瘤消退。在这里，我们表明，这些途径相互调节的相互负反馈，这样的抑制一个激活其他。因此，肿瘤细胞可以适应和生存时，任何一个单一的途径被抑制。我们在临床前前列腺肿瘤模型中证明了联合途径抑制的显著肿瘤消退，为患者的联合治疗提供了理论基础。
Prostate cancer is characterized by its dependence on androgen receptor and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival. The two most frequently activated signaling pathways in prostate cancer are driven by AR and PI3K. Inhibitors of the PI3K pathway are in early clinical trials and AR inhibitors confer clinical responses in most patients. However, these inhibitors rarely induce tumor regression in preclinical models. Here we show that these pathways regulate each other by reciprocal negative feedback, such that inhibition of one activates the other. Therefore, tumor cells can adapt and survive when either single pathway is inhibited pharmacologically. Our demonstration of profound tumor regressions with combined pathway inhibition in preclinical prostate tumor models provides rationale for combination therapy in patients.
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多种致癌途径特征显示人类前列腺肿瘤中的坐标表达模式。
影响因子：
3.7
作者：
Creighton, Chad J.
通讯作者：
Creighton, Chad J.
DOI：
10.1073/pnas.0700420104
发表时间：
2007-05-15
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
82.9
作者：
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通讯作者：
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影响因子：
10.5
作者：
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通讯作者：
Hay, Nissim