Myoglobin induces mitochondrial fusion, thereby inhibiting breast cancer cell proliferation
Myoglobin induces mitochondrial fusion, thereby inhibiting breast cancer cell proliferation
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DOI：
10.1074/jbc.ra118.006673
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发表时间：
2019-05-03
影响因子：
4.8
通讯作者：
Shiva, Sruti
中科院分区：
文献类型：
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作者：
Braganza, Andrea;Quesnelle, Kelly;Shiva, Sruti
肌红蛋白是一种在骨骼肌和心肌中普遍表达的单体血红素蛋白，传统上认为它在缺氧时是线粒体的氧库。现在已经确定，低浓度的肌红蛋白在很大比例的乳腺癌肿瘤中异常表达。尽管在这些肿瘤中肌红蛋白的表达水平较低，但在乳腺癌患者中，肌红蛋白与肿瘤生长减弱和预后改善有关，但这种肌红蛋白介导的防止癌症进一步生长的机制尚不清楚。在这里，我们报告了肌红蛋白调节线粒体动力学从而减少细胞增殖的信号通路。我们在体外证明，人肌红蛋白在MDA-MB-231、MDA-MB-468和MCF7乳腺癌细胞中的表达通过上调线粒体融合蛋白1和2（线粒体融合的主要催化剂）诱导线粒体低灌注。这种低灌注引起细胞周期阻滞和随后的细胞增殖抑制。从机制上讲，丝裂酶表达的增加是由于肌红蛋白依赖性自由基的产生，导致E3泛素连接酶parkin的氧化和降解。我们在小鼠模型中总结了这一途径，在小鼠模型中，表达肌红蛋白的异种移植物表现出肿瘤体积减少，有丝分裂蛋白增加，细胞周期停滞的标志，帕金蛋白表达减少。此外，在人类三阴性乳腺肿瘤组织中，有丝分裂酶和肌红蛋白水平呈正相关。总的来说，这些结果阐明了肌红蛋白作为线粒体动力学调节剂的新功能，并揭示了肌红蛋白通过上调丝裂酶水平来降低乳腺癌细胞增殖和肿瘤生长的新途径。
Myoglobin is a monomeric heme protein expressed ubiquitously in skeletal and cardiac muscle and is traditionally considered to function as an oxygen reservoir for mitochondria during hypoxia. It is now well established that low concentrations of myoglobin are aberrantly expressed in a significant proportion of breast cancer tumors. Despite being expressed only at low levels in these tumors, myoglobin is associated with attenuated tumor growth and a better prognosis in breast cancer patients, but the mechanism of this myoglobin-mediated protection against further cancer growth remains unclear. Herein, we report a signaling pathway by which myoglobin regulates mitochondrial dynamics and thereby decreases cell proliferation. We demonstrate in vitro that expression of human myoglobin in MDA-MB-231, MDA-MB-468, and MCF7 breast cancer cells induces mitochondrial hyperfusion by up-regulating mitofusins 1 and 2, the predominant catalysts of mitochondrial fusion. This hyperfusion causes cell cycle arrest and subsequent inhibition of cell proliferation. Mechanistically, increased mitofusin expression was due to myoglobin-dependent free-radical production, leading to the oxidation and degradation of the E3 ubiquitin ligase parkin. We recapitulated this pathway in a murine model in which myoglobin-expressing xenografts exhibited decreased tumor volume with increased mitofusin, markers of cell cycle arrest, and decreased parkin expression. Furthermore, in human triple-negative breast tumor tissues, mitofusin and myoglobin levels were positively correlated. Collectively, these results elucidate a new function for myoglobin as a modulator of mitochondrial dynamics and reveal a novel pathway by which myoglobin decreases breast cancer cell proliferation and tumor growth by up-regulating mitofusin levels.