Loss of COX5B inhibits proliferation and promotes senescence via mitochondrial dysfunction in breast cancer.
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. Down-regulation 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.
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Shui-Ping
SP
Gao
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
He-Fen
HF
Sun
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Hong-Lin
HL
Jiang
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Liang-Dong
LD
Li
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.
Xin
X
Hu
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Xiao-En
XE
Xu
Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Wei
W
Jin
D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D003576:Electron Transport Complex IV / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection
D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C480024:COX5B protein, human; D003576:Electron Transport Complex IV
COX5B; cytokine; mitochondrial dysfunction; proliferation; senescence