MFN2 suppresses cancer progression through inhibition of mTORC2/Akt signaling.
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 AktS437phosphorylation 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.
Central laboratory, General Surgery, Putuo Hospital, and Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 164 Lanxi Rd, Shanghai 200062, PR China.
Ke
K
Xu
Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
Guo
G
Chen
Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
Xiaobo
X
Li
School of Pharmacy, Institute for Liver Diseases of Anhui Medical University, ILDAMU, Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Hefei, 230032, China.
Xiaoqin
X
Wu
State Key Laboratory of Membrane Biology, School of Medicine, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Zhijie
Z
Chang
Central laboratory, General Surgery, Putuo Hospital, and Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 164 Lanxi Rd, Shanghai 200062, PR China.
Jianhua
J
Xu
Department of Clinical Laboratory, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vessels and Neural Degeneration, Tianjin 300350, China.
Yu
Y
Zhu
Central laboratory, General Surgery, Putuo Hospital, and Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 164 Lanxi Rd, Shanghai 200062, PR China.
Peihao
P
Yin
State Key Laboratory of Bioreactor Engineering &Shanghai Key Laboratory of New drug design, School of pharmacy, East China University of Science and Technology, 130 Meilong Rd, Shanghai 200237, PR China.
Xin
X
Liang
Central laboratory, General Surgery, Putuo Hospital, and Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 164 Lanxi Rd, Shanghai 200062, PR China.|Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.|Department of Pediatrics, Division of Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322, USA.
Lei
L
Dong
D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D055786:Gene Knockout Techniques; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism*; D008546:Melanoma, Experimental; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden
D024101:Mitochondrial Proteins; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human