Knockdown of PGC1α suppresses dysplastic oral keratinocytes proliferation through reprogramming energy metabolism  

作　　者：Yunkun Liu Nengwen Huang Xianghe Qiao Zhiyu Gu Yongzhi Wu Jinjin Li Chengzhou Wu Bo Li Longjiang Li 

机构地区：[1]State Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Department of Head and Neck Oncology,West China Hospital of Stomatology,Sichuan University,Chengdu,China [2]Department of Preventive and Pediatric Dentistry,Hospital of Stomatology,Zunyi Medical University,Zunyi,China [3]State Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Department of Orthodontics,West China Hospital of Stomatology,Sichuan University,Chengdu,China

出　　处：《International Journal of Oral Science》2023年第3期502-512,共11页国际口腔科学杂志（英文版）

基　　金：supported by the National Natural Science Foundations of China(82372735,82141130).

摘　　要：Oral potentially malignant disorders(OPMDs)are precursors of oral squamous cell carcinoma(OSCC).Deregulated cellular energy metabolism is a critical hallmark of cancer cells.Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha(PGC1α)plays vital role in mitochondrial energy metabolism.However,the molecular mechanism of PGC1αon OPMDs progression is less unclear.Therefore,we investigated the effects of knockdown PGC1αon human dysplastic oral keratinocytes(DOKs)comprehensively,including cell proliferation,cell cycle,apoptosis,xenograft tumor,mitochondrial DNA(mtDNA),mitochondrial electron transport chain complexes(ETC),reactive oxygen species(ROS),oxygen consumption rate(OCR),extracellular acidification rate(ECAR),and glucose uptake.We found that knockdown PGC1αsignificantly inhibited the proliferation of DOKs in vitro and tumor growth in vivo,induced S-phase arrest,and suppressed PI3K/Akt signaling pathway without affecting cell apoptosis.Mechanistically,downregulated of PGC1αdecreased mtDNA,ETC,and OCR,while enhancing ROS,glucose uptake,ECAR,and glycolysis by regulating lactate dehydrogenase A(LDHA).Moreover,SR18292(an inhibitor of PGC1α)induced oxidative phosphorylation dysfunction of DOKs and declined DOK xenograft tumor progression.Thus,our work suggests that PGC1αplays a crucial role in cell proliferation by reprograming energy metabolism and interfering with energy metabolism,acting as a potential therapeutic target for OPMDs.

关 键 词：METABOLISM energy OCR 

分 类 号：R730.2[医药卫生—肿瘤]