Src family kinases (SFKs) play a crucial role in the regulation of multiple cellular pathways, including mitochondrial oxidative phosphorylation (OXPHOS). Aberrant activities of one of the most predominant SFKs, c-Src, was identified as a fundamental cause for dysfunctional cell signaling and implicated in cancer development and metastasis, especially in human hepatocellular carcinoma (HCC). Recent work in our laboratory revealed that c-Src is implicated in the regulation of mitochondrial energy metabolism in cancer. In this study, we investigated the effect of c-Src expression on mitochondrial energy metabolism by examining changes in the expression and activities of OXPHOS complexes in liver cancer biopsies and cell lines. An increased expression of c-Src was correlated with an impaired expression of nuclear- and mitochondrial-encoded subunits of OXPHOS complexes I and IV, respectively, in metastatic biopsies and cell lines. Additionally, we observed a similar association between high c-Src and reduced OXPHOS complex expression and activity in mouse embryonic fibroblast (MEF) cell lines. Interestingly, the inhibition of c-Src kinase activity with the SFK inhibitor PP2 and c-Src siRNA stimulated the expression of complex I and IV subunits and increased their enzymatic activities in both cancer and normal cells. Evidence provided in this study reveals that c-Src impairs the expression and function of mitochondrial OXPHOS complexes, resulting in a significant defect in mitochondrial energy metabolism, which can be a contributing factor to the development and progression of liver cancer. Furthermore, our findings strongly suggest that SFK inhibitors should be used in the treatment of HCC and other cancers with aberrant c-Src kinase activity to improve mitochondrial energy metabolism.

中文翻译：

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c-Src 激酶损害肝癌中线粒体 OXPHOS 复合物的表达。

Src 家族激酶 (SFK) 在多种细胞途径的调节中发挥着至关重要的作用，包括线粒体氧化磷酸化 (OXPHOS)。最主要的 SFK 之一 c-Src 的异常活动被确定为功能失调的细胞信号传导的根本原因，并与癌症发展和转移有关，特别是在人类肝细胞癌 (HCC) 中。我们实验室最近的工作表明，c-Src 与癌症中线粒体能量代谢的调节有关。在这项研究中，我们通过检查肝癌活检和细胞系中 OXPHOS 复合物的表达和活性的变化来研究 c-Src 表达对线粒体能量代谢的影响。在转移活检和细胞系中，c-Src 的表达增加与 OXPHOS 复合物 I 和 IV 的核和线粒体编码亚基的表达受损相关。此外，我们在小鼠胚胎成纤维细胞 (MEF) 细胞系中观察到高 c-Src 与降低的 OXPHOS 复合物表达和活性之间存在类似的关联。有趣的是，SFK 抑制剂 PP2 和 c-Src siRNA 对 c-Src 激酶活性的抑制刺激了复合物 I 和 IV 亚基的表达，并增加了它们在癌细胞和正常细胞中的酶活性。本研究提供的证据表明，c-Src 会损害线粒体 OXPHOS 复合物的表达和功能，导致线粒体能量代谢出现显着缺陷，这可能是肝癌发展和进展的一个促成因素。此外，我们的研究结果强烈表明，SFK 抑制剂应用于治疗 HCC 和其他具有异常 c-Src 激酶活性的癌症，以改善线粒体能量代谢。