Although mitochondrial metabolism has recently gained attention as a promising therapeutic strategy in cancer, little is known on the impact of mitochondrial respiration inhibition on oral tongue squamous cell carcinoma (OTSCC). Using in vitro and in vivo OTSCC models, our work demonstrates that inducing mitochondrial dysfunction by anti-malarial drug artesunate is effective in targeting OTSCC stem-cell like and bulk cells. Artesunate inhibits anchorage-independent colony formation, proliferation and survival in all tested OTSCC cell lines although with varying efficacy. Artesunate displays preferential anti-OTSCC activity by sparing normal cells. Mechanism analysis indicates that artesunate inhibits mitochondrial respiration via suppressing mitochondrial complex I and II but not IV or V, resulting in oxidative stress and damage. Interestingly, OTSCC cells that are more sensitive to artesunate have higher level of basal mitochondrial respiration and reversed respiratory capacity compared to those with less sensitivity to artesunate, suggesting the varying dependence on mitochondrial respiration among OTSCC cell lines. In addition, artesunate induces oxidative stress and damage in cells with low sensitivity to a less extent than in those with high sensitivity. We confirm that mitochondrial respiration inhibition is required for the action of artesunate in OTSCC. Mitochondrial dysfunction by artesunate further activates AMPK and suppresses Akt/mTOR. Importantly, the in vitro observations are reproducible in vivo OTSCC xenograft mouse model. Our findings provide pre-clinical evidence on the efficacy of artesunate and emphasize the therapeutic value of targeting mitochondrial respiration in OTSCC.

中文翻译：

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青蒿琥酯通过线粒体功能障碍依赖性氧化损伤和Akt / AMPK / mTOR抑制作用靶向舌鳞状细胞癌。

尽管线粒体代谢最近已作为一种有前途的癌症治疗方法受到关注，但对线粒体呼吸抑制对口腔鳞状细胞癌（OTSCC）的影响知之甚少。使用体外和体内OTSCC模型，我们的工作证明，抗疟药青蒿琥酯诱导线粒体功能障碍可有效靶向OTSCC干细胞样细胞和大细胞。青蒿琥酯在所有测试的OTSCC细胞系中均抑制了不依赖于贴壁的集落形成，增殖和存活，尽管功效不同。青蒿琥酯通过保留正常细胞显示出优先的抗OTSCC活性。机理分析表明，青蒿琥酯通过抑制线粒体复合体I和II，但不抑制IV或V抑制线粒体呼吸，导致氧化应激和损伤。有趣的是 与对青蒿琥酯敏感性较低的OTSCC细胞相比，对青蒿琥酯更敏感的OTSCC细胞具有更高水平的线粒体基础呼吸和反向呼吸能力，这表明OTSCC细胞系对线粒体呼吸的依赖性不同。此外，青蒿琥酯在低敏感性细胞中诱导氧化应激和损伤的程度比高敏感性细胞低。我们证实线粒体呼吸抑制是青蒿琥酯在OTSCC中的作用所必需的。青蒿琥酯的线粒体功能障碍会进一步激活AMPK，并抑制Akt / mTOR。重要的是，体外观察结果可在体内OTSCC异种移植小鼠模型中重现。