α3β1 Integrin Suppresses Prostate Cancer Metastasis via Regulation of the Hippo Pathway.
α3β1 Integrin Suppresses Prostate Cancer Metastasis via Regulation of the Hippo Pathway.
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DOI：
10.1158/0008-5472.can-16-1483
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发表时间：
2016-11-15
期刊：
影响因子：
11.2
通讯作者：
Stipp CS
中科院分区：
文献类型：
--
作者：
Varzavand A;Hacker W;Ma D;Gibson-Corley K;Hawayek M;Tayh OJ;Brown JA;Henry MD;Stipp CS
现有的抗癌策略侧重于破坏肿瘤细胞或肿瘤相关内皮细胞中的整合素功能，但取得的成功有限。另一种策略是增强整合素介导的抑制肿瘤进展的途径，但整合素如何发出信号来抑制恶性行为仍不清楚。为了解决这个问题，我们通过消耗 α3β1 整合素建立了前列腺癌转移的体内模型，这种相关性在很大一部分前列腺癌中观察到。我们的数据描述了一种机制，α3β1 通过 Abl 家族激酶发出信号来抑制 Rho GTPase 活性，支持 Hippo 通路抑制功能，并抑制前列腺癌迁移、侵袭和锚定依赖性生长。这种α3β1-Abl激酶-Hippo抑制通路将α3整合素缺陷型前列腺癌鉴定为目前正在开发的Hippo靶向疗法的潜在候选者，这提出了基于整合素表达的针对转移性前列腺癌的新策略。我们的数据还揭示了前列腺癌中 Abl 激酶的矛盾肿瘤抑制功能，这可能有助于解释 Abl 激酶抑制剂伊马替尼在前列腺癌临床试验中的失败。
Existing anti-cancer strategies focused on disrupting integrin functions in tumor cells or tumor-involved endothelial cells have met limited success. An alternative strategy is to augment integrin-mediated pathways that suppress tumor progression, but how integrins can signal to restrain malignant behavior remains unclear. To address this issue, we generated an in vivo model of prostate cancer metastasis via depletion of α3β1 integrin, a correlation observed in a significant proportion of prostate cancers. Our data describe a mechanism whereby α3β1 signals through Abl family kinases to restrain Rho GTPase activity, support Hippo pathway suppressor functions, and restrain prostate cancer migration, invasion, and anchorage-independent growth. This α3β1-Abl kinase-Hippo suppressor pathway identified α3 integrin-deficient prostate cancers as potential candidates for Hippo-targeted therapies currently under development, suggesting new strategies for targeting metastatic prostate cancer based on integrin expression. Our data also revealed paradoxical tumor suppressor functions for Abl kinases in prostate cancer that may help to explain the failure of Abl kinase inhibitor imatinib in prostate cancer clinical trials.