Depletion of mitochondrial protease OMA1 alters proliferative properties and promotes metastatic growth of breast cancer cells
Depletion of mitochondrial protease OMA1 alters proliferative properties and promotes metastatic growth of breast cancer cells
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DOI：
10.1038/s41598-019-49327-2
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发表时间：
2019-10-14
影响因子：
4.6
通讯作者：
Kidambi, Srivatsan
中科院分区：
文献类型：
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作者：
Daverey, Amita;Levytskyy, Roman M.;Kidambi, Srivatsan
癌细胞的转移能力受到许多因素的影响，包括代谢改变和线粒体的变化！生物发生和蛋白质稳态。虽然普遍认为线粒体在肿瘤发生中起重要作用，但调节异常癌细胞增殖的相应分子事件仍有待澄清。因此，了解线粒体在癌症进展中的作用机制对开发新的治疗策略具有潜在意义。我们发现线粒体的低表达！质量控制蛋白酶OMA 1与乳腺癌患者总体生存率低相关。在从转移性胸腔积液和非典型导管增生乳腺肿瘤标本（21 MT-1和21 PT）中分离的患者来源的转移性乳腺癌细胞中，体外沉默OMA 1可增强丝状伪足的形成，增加细胞增殖（Ki 67表达），并诱导上皮-间质转化（EMT）。从机制上讲，OMA 1的丢失会导致线粒体的改变！蛋白质稳态，如通过增强的典型线粒体表达所反映的！未折叠蛋白反应基因。这些变化显著增加了转移性乳腺癌细胞的迁移特性，表明OMA 1在抑制乳腺肿瘤的转移能力中起着关键作用。有趣的是，在OMA 1耗尽的非致瘤性MCF 10A乳腺上皮细胞中未观察到这些结果。这种新发现的OMA 1活性/水平降低提供了对导致乳腺癌发展、促进癌细胞恶性进展和不利临床结果的机制的见解，这可能代表乳腺癌治疗的可能预后标志物和治疗靶点。
Metastatic competence of cancer cells is influenced by many factors including metabolic alterations and changes in mitochondria! biogenesis and protein homeostasis. While it is generally accepted that mitochondria play important roles in tumorigenesis, the respective molecular events that regulate aberrant cancer cell proliferation remain to be clarified. Therefore, understanding the mechanisms underlying the role of mitochondria in cancer progression has potential implications in the development of new therapeutic strategies. We show that low expression of mitochondria! quality control protease OMA1 correlates with poor overall survival in breast cancer patients. Silencing OMA1 in vitro in patient-derived metastatic breast cancer cells isolated from the metastatic pleural effusion and atypical ductal hyperplasia mammary tumor specimens (21MT-1 and 21PT) enhances the formation of filopodia, increases cell proliferation (Ki67 expression), and induces epithelial-mesenchymal transition (EMT). Mechanistically, loss of OMA1 results in alterations in the mitochondria! protein homeostasis, as reflected by enhanced expression of canonic mitochondria! unfolded protein response genes. These changes significantly increase migratory properties in metastatic breast cancer cells, indicating that OMA1 plays a critical role in suppressing metastatic competence of breast tumors. Interestingly, these results were not observed in OMA1-depleted non-tumorigenic MCF10A mammary epithelial cells. This newly identified reduced activity/levels of OMA1 provides insights into the mechanisms leading to breast cancer development, promoting malignant progression of cancer cells and unfavorable clinical outcomes, which may represent possible prognostic markers and therapeutic targets for breast cancer treatment.