Loss of COX5B inhibits proliferation and promotes senescence via mitochondrial dysfunction in breast cancer
Loss of COX5B inhibits proliferation and promotes senescence via mitochondrial dysfunction in breast cancer
复制标题
乳腺癌中 COX5B 的缺失会通过线粒体功能障碍抑制增殖并促进衰老
DOI：
10.18632/oncotarget.6222
复制
发表时间：
2015-12-22
期刊：
影响因子：
--
通讯作者：
Jin, Wei
中科院分区：
文献类型：
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作者：
Gao, Shui-Ping;Sun, He-Fen;Jin, Wei
COX5B是细胞色素c氧化酶复合物的外周亚基，以前曾报道可维持该复合物的稳定性。然而，其参与乳腺癌进展的功能和机制仍不清楚。在这里，通过在乳腺癌细胞模型中进行SILAC测定并检测组织中的COX5B表达，我们发现COX5B表达在乳腺癌中升高。COX5B在乳腺癌细胞系中的下调可以抑制细胞增殖并诱导细胞衰老，这伴随着IL-8和其他细胞因子的产生增加。有趣的是，来自COX5B敲低细胞的条件培养基可以促进乳腺癌细胞迁移。机制研究表明，COX5B沉默诱导ROS产生增加，MMP去极化和ATP减少。更重要的是，COX5B的沉默导致代谢紊乱，如葡萄糖摄取增加和乳酸分泌减少。总的来说，我们的研究表明，COX5B的丢失诱导线粒体功能障碍，随后导致细胞生长抑制和细胞衰老。细胞因子如由衰老细胞分泌的IL-8可以反过来改变微环境，这可以增强细胞迁移。这些发现可能为联合抗癌药物和特定细胞因子抑制剂（如IL-8阻断剂）的治疗提供了一种新的范式。
COX5B, a peripheral subunit of the cytochrome c oxidase complex, has previously been reported to maintain the stability of this complex. However, its functions and mechanisms involved in breast cancer progression remain unclear. Here, by performing SILAC assays in breast cancer cell models and detecting COX5B expression in tissues, we found that COX5B expression was elevated in breast cancer. Downregulation of COX5B in breast cancer cell lines can suppress cell proliferation and induced cell senescence which was accompanied by elevating production of IL-8 and other cytokines. Interestingly, conditioned medium from COX5B knockdown cells could promote breast cancer cell migration. Mechanistic studies reveal that COX5B silence induces an increase in production of ROS, depolarization of MMP and a decrease in ATP. What's more, silence of COX5B leads to metabolic disorders, such as increased glucose uptake and decreased lactate secretion. Collectively, our study shows that loss of COX5B induces mitochondrial dysfunction and subsequently leads to cell growth suppression and cell senescence. Cytokines such as IL-8 secreted by senescent cells may in turn alter the microenvironment which could enhance cell migration. These findings may provide a novel paradigm for the treatment which combined anti-cancer drugs with particular cytokine inhibitors such as IL-8 blockers.