Enhanced MET Translation and Signaling Sustains K-Ras-Driven Proliferation under Anchorage-Independent Growth Conditions.
Enhanced MET Translation and Signaling Sustains K-Ras-Driven Proliferation under Anchorage-Independent Growth Conditions.
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DOI：
10.1158/0008-5472.can-14-1623
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发表时间：
2015-07-15
期刊：
影响因子：
11.2
通讯作者：
McCormick F
中科院分区：
文献类型：
--
作者：
Fujita-Sato S;Galeas J;Truitt M;Pitt C;Urisman A;Bandyopadhyay S;Ruggero D;McCormick F
致癌性K-Ras突变经常发生在几种类型的癌症中，包括胰腺癌和肺癌。具有K-Ras突变的肿瘤对化疗药物以及分子靶向剂具有抗性。尽管许多方法正在寻找治疗这些肿瘤的有效方法，但仍然没有针对K-Ras突变癌症患者的有效疗法。在这里，我们报告说，K-Ras突变的癌症更依赖于K-Ras在锚定非依赖性培养条件比在单层培养条件。在寻求确定在锚定非依赖性培养条件下有助于K-Ras依赖性的机制时，我们发现Met参与K-Ras依赖性、锚定非依赖性细胞生长。Met信号传导途径被增强，并且即使在Met未被扩增的细胞中也在锚定非依赖性生长中发挥不可或缺的作用。事实上，Met表达在锚定非依赖性生长条件下升高，并且以MAPK/ERK激酶（MEK）依赖性方式由K-Ras调节。值得注意的是，尽管在锚定非依赖性生长过程中mRNA翻译的整体下调，我们发现Met mRNA翻译在这些条件下特异性增强。重要的是，活性Met突变体的异位表达挽救了K-Ras消融衍生的生长抑制，表明K-Ras介导的Met表达在锚定非依赖性条件下驱动“K-Ras成瘾”。我们的研究结果表明，增强的Met表达和信号传导对于K-Ras突变癌细胞的锚定非依赖性生长至关重要，并表明Met的药理学抑制剂对K-Ras突变肿瘤患者可能有效。
Oncogenic K-Ras mutation occurs frequently in several types of cancers including pancreatic and lung cancers. Tumors with K-Ras mutation are resistant to chemotherapeutic drugs as well as molecular targeting agents. Although numerous approaches are ongoing to find effective ways to treat these tumors, there are still no effective therapies for K-Ras mutant cancer patients. Here we report that K-Ras mutant cancers are more dependent on K-Ras in anchorage independent culture conditions than in monolayer culture conditions. In seeking to determine mechanisms that contribute to the K-Ras dependency in anchorage independent culture conditions, we discovered the involvement of Met in K-Ras-dependent, anchorage independent cell growth. The Met signaling pathway is enhanced and plays an indispensable role in anchorage independent growth even in cells in which Met is not amplified. Indeed, Met expression is elevated under anchorage-independent growth conditions and is regulated by K-Ras in a MAPK/ERK kinase (MEK)-dependent manner. Remarkably, in spite of a global down-regulation of mRNA translation during anchorage independent growth, we find that Met mRNA translation is specifically enhanced under these conditions. Importantly, ectopic expression of an active Met mutant rescues K-Ras ablation-derived growth suppression, indicating that K-Ras mediated Met expression drives “K-Ras addiction” in anchorage independent conditions. Our results indicate that enhanced Met expression and signaling is essential for anchorage independent growth of K-Ras mutant cancer cells and suggests that pharmacological inhibitors of Met could be effective for K-Ras mutant tumor patients.