Abstract：
The functional importance of mitochondrial protein translation has been recently documented in the context of various cancers but not renal cell carcinoma (RCC). In lines with these efforts, our work demonstrates that mitochondrial translation inhibition by tigecycline or depletion of EF-Tu mitochondrial translation factor effectively targets RCC and significantly sensitizes RCC response to chemotherapy. We show that antibiotic tigecycline inhibits multiple biological functions of RCC, including growth, colony formation and survival. It also significantly enhances in vitro and in vivo efficacy of paclitaxel in RCC. Tigecycline preferentially inhibits translation of mitochondrial DNA-encoded proteins, activities of mitochondrial respiratory complexes that contain mitochondrially encoded subunits. As a consequence of mitochondrial respiratory chain inhibition, decreased mitochondrial respiration is observed in RCC cells exposed to tigecycline. In contrast, tigecycline is ineffective in RCC ρ0 cells that lack mitochondrial DNA and subsequent mitochondrial respiration, further confirm mitochondrial translation inhibition as the mechanism of tigecycline\'s action in RCC. Importantly, genetic inhibition of mitochondrial translation by EF-Tu knockdown reproduced the inhibitory effects of tigecycline. Finally, we show the association between mitochondrial translation inhibition and suppression of PI3K/Akt/mTOR signaling pathway. Our work used pharmacological and genetic strategies to demonstrate the important roles of mitochondrial translation in RCC and emphasize the therapeutic value of sensitizing RCC to chemotherapy.
摘要：
线粒体蛋白质翻译的功能重要性最近已在各种癌症而不是肾细胞癌（RCC）的背景下得到证明。根据这些努力，我们的工作表明,替加环素对线粒体翻译的抑制或EF-Tu线粒体翻译因子的缺失可有效靶向RCC,并显著提高RCC对化疗的敏感性.我们表明抗生素替加环素抑制RCC的多种生物学功能，包括增长,集落的形成和生存。它还显著增强紫杉醇在RCC中的体外和体内功效。替加环素优先抑制线粒体DNA编码蛋白的翻译，含有线粒体编码亚基的线粒体呼吸复合物的活性。作为线粒体呼吸链抑制的结果，在暴露于替加环素的RCC细胞中观察到线粒体呼吸减少。相比之下,替加环素在缺乏线粒体DNA和随后的线粒体呼吸的RCCρ0细胞中无效，进一步证实线粒体翻译抑制是替加环素在RCC中的作用机制。重要的是,EF-Tu敲除对线粒体翻译的遗传抑制再现了替加环素的抑制作用。最后,我们显示了线粒体翻译抑制与PI3K/Akt/mTOR信号通路抑制之间的关联。我们的工作使用药理学和遗传学策略来证明线粒体翻译在RCC中的重要作用，并强调了使RCC对化疗敏感的治疗价值。
