New York University Langone School of Medicine, New York, NY, United States of America.
PLoS One. 2013 Nov 29;8(11):e83395. doi: 10.1371/journal.pone.0083395. eCollection 2013.
Activating mutations in the RasGTPases are the most common oncogenic lesions in human cancer. Similarly, elevated STAT3 expression and/or phosphorylation are observed in the majority of human cancers. We recently found that activated Ras requires a mitochondrial rather than a nuclear activity of STAT3 to support cellular transformation. This mitochondrial activity of STAT3 was supported by phosphorylation on serine 727 (S727) in the carboxyl-terminus of STAT3. In this study we show that the H-Ras oncoprotein engages the MEK-ERK pathway to drive phosphorylation of STAT3 on S727, while phosphoinositide 3-kinase (PI3K) and mTOR activity were superfluous. Moreover, pharmacological inhibition of MEK reduced transformation by H-, K- or N-Ras. However, cells expressing a mitochondrially restricted STAT3 with a phospho-mimetic mutation at S727 were partially resistant to inhibition of the ERK pathway, exhibiting a partial rescue of anchorage-independent cell growth in the presence of MEK inhibitor. This study shows that the MEK-ERK pathway is required for activated Ras-induced phosphorylation of STAT3 on S727, that inhibition of STAT3 S727 phosphorylation contributes to the anti-oncogenic potential of MEK inhibitors, and that mitochondrial STAT3 is one of the critical substrates of the Ras-MEK-ERK- axis during cellular transformation.
RasGTPases 的激活突变是人类癌症中最常见的致癌病变。同样，在大多数人类癌症中观察到 STAT3 表达和/或磷酸化水平升高。我们最近发现，激活的 Ras 需要 STAT3 的线粒体而非核活性来支持细胞转化。STAT3 的这种线粒体活性得到 STAT3 羧基末端丝氨酸 727（S727）磷酸化的支持。在这项研究中，我们表明 H-Ras 癌蛋白通过 MEK-ERK 途径参与驱动 STAT3 上 S727 的磷酸化，而磷酸肌醇 3-激酶（PI3K）和 mTOR 活性是多余的。此外，MEK 的药理学抑制减少了 H-、K-或 N-Ras 的转化。然而，表达 S727 磷酸化模拟突变的线粒体受限 STAT3 的细胞对 ERK 途径的抑制具有部分抗性，在存在 MEK 抑制剂的情况下，对锚定非依赖性细胞生长具有部分挽救作用。这项研究表明，MEK-ERK 途径是激活的 Ras 诱导 STAT3 上 S727 磷酸化所必需的，抑制 STAT3 S727 磷酸化有助于 MEK 抑制剂的抗癌潜力，并且线粒体 STAT3 是细胞转化过程中 Ras-MEK-ERK 轴的关键底物之一。
