title: Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways.
abstract: Mitochondrial morphology is dynamically remodeled by fusion and fission in cells, and dysregulation of this process is closely implicated in tumorigenesis. However, the mechanism by which mitochondrial dynamics influence cancer cell survival is considerably less clear, especially in hepatocellular carcinoma (HCC). In this study, we systematically investigated the alteration of mitochondrial dynamics and its functional role in the regulation of autophagy and HCC cell survival. Furthermore, the underlying molecular mechanisms and therapeutic application were explored in depth. Mitochondrial fission was frequently upregulated in HCC tissues mainly due to an elevated expression ratio of DNM1L to MFN1, which significantly contributed to poor prognosis of HCC patients. Increased mitochondrial fission by forced expression of DNM1L or knockdown of MFN1 promoted the survival of HCC cells both in vitro and in vivo mainly by facilitating autophagy and inhibiting mitochondria-dependent apoptosis. We further demonstrated that the survival-promoting role of increased mitochondrial fission was mediated via elevated ROS production and subsequent activation of AKT, which facilitated MDM2-mediated TP53 degradation, and NFKBIA- and IKK-mediated transcriptional activity of NFKB in HCC cells. Also, a crosstalk between TP53 and NFKB pathways was involved in the regulation of mitochondrial fission-mediated cell survival. Moreover, treatment with mitochondrial division inhibitor-1 significantly suppressed tumor growth in an in vivo xenograft nude mice model. Our findings demonstrate that increased mitochondrial fission plays a critical role in regulation of HCC cell survival, which provides a strong evidence for this process as drug target in HCC treatment.
authors.affiliation: a State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University , Xi'an , China.
authors.forename: Qichao
authors.initials: Q
authors.lastname: Huang
authors.affiliation: b Department of Gastroenterology , Second Affiliated Hospital of Harbin Medical University , Harbin , China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhan
authors.affiliation: a State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University , Xi'an , China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Cao
authors.affiliation: a State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University , Xi'an , China.
authors.forename: Jibin
authors.initials: J
authors.lastname: Li
authors.affiliation: a State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University , Xi'an , China.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Lyu
authors.affiliation: a State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University , Xi'an , China.
authors.forename: Xu
authors.initials: X
authors.lastname: Guo
authors.affiliation: a State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University , Xi'an , China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: a State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University , Xi'an , China.
authors.forename: Lele
authors.initials: L
authors.lastname: Ji
authors.affiliation: a State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University , Xi'an , China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Ren
authors.affiliation: c Department of Hepatobiliary Surgery , Xijing Hospital, Fourth Military Medical University , Xi'an , China.
authors.forename: Jiaze
authors.initials: J
authors.lastname: An
authors.affiliation: b Department of Gastroenterology , Second Affiliated Hospital of Harbin Medical University , Harbin , China.
authors.forename: Bingrong
authors.initials: B
authors.lastname: Liu
authors.affiliation: d State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University , Xi'an , China.
authors.forename: Yongzhan
authors.initials: Y
authors.lastname: Nie
authors.affiliation: a State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University , Xi'an , China.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Xing
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D034281:Dynamins; D005260:Female; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008875:Middle Aged; D063154:Mitochondrial Dynamics / Q000187:drug effects; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011379:Prognosis; D052999:Quinazolinones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D052999:Quinazolinones; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: apoptosis; autophagy; cell survival; liver cancer; mitochondrial dynamics