The mitochondrial GTPase mitofusin-2 (MFN2) has previously been reported to play a role in regulating cell proliferation, apoptosis and differentiation in a number of cell types. Here, we report that breast cancer patients with low MFN2 expression are associated with poor prognosis as compared to patients with high MFN2 expression. We find that MFN2 knockout from MCF7 and A549 cells via Crispr/Cas9 greatly promotes cell viability, colony formation, and invasion of cancer cells in vitro and in vivo, which were confirmed by colony formation assay, transwell invasion assay, and tumor xenograft model. Signaling analyses suggest the mammalian target of rapamycin complex 2 (mTORC2)/Akt signaling pathway is highly elevated in MFN2 knockout cancer cells. The elevated mTORC2 promotes cancer cell growth and metastasis via AktS(437) phosphorylation mediated signaling pathway. Mechanistic studies reveal that MFN2 suppresses mTORC2 through direct interaction by binding its domain HR1. Inhibition of mTORC2 significantly suppresses MFN2 deficient tumor growth. Collectively, this study provides novel insights into the tumor progression associated with MFN2 deficiency and suggests that the importance of mTORC2 inhibitor in the treatment of MFN2 downregulated cancer patients.
[1]Shanghai Univ Tradit Chinese Med, Putuo Hosp, Cent Lab, Gen Surg, 164 Lanxi Rd, Shanghai 200062, Peoples R China.
[2]Shanghai Univ Tradit Chinese Med, Canc Inst Chinese Integrat Med, 164 Lanxi Rd, Shanghai 200062, Peoples R China.
[3]Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA 30322 USA.
[4]Tianjin Inst Pharmaceut Res, Tianjin Key Lab Mol Design & Drug Discovery, Tianjin 300193, Peoples R China.
[5]Anhui Med Univ, Sch Pharm, Inst Liver Dis, Key Lab Antiinflammatory & Immune Med,IL DAMU, Hefei 230032, Peoples R China.
[6]Tsinghua Univ, Sch Med, Sch Life Sci, State Key Lab Membrane Biol, Beijing 100084, Peoples R China.
[7]Tianjin Huanhu Hosp, Dept Clin Lab, Tianjin Key Lab Cerebral Vessels & Neural Degener, Tianjin 300350, Peoples R China.
[8]East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, 130 Meilong Rd, Shanghai 200237, Peoples R China.
[9]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Meilong Rd, Shanghai 200237, Peoples R China.
[10]Emory Univ, Sch Med, Childrens Healthcare Atlanta, Aflac Canc & Blood Disorders Ctr,Dept Pediat,Div, Atlanta, GA 30322 USA.
(8.0+极速模式)