Knockdown of PGC1α suppresses dysplastic oral keratinocytes proliferation through reprogramming energy metabolism.
10.1038/s41368-023-00242-3
- Author:
Yunkun LIU
1
;
Nengwen HUANG
1
;
Xianghe QIAO
1
;
Zhiyu GU
2
;
Yongzhi WU
1
;
Jinjin LI
1
;
Chengzhou WU
1
;
Bo LI
3
;
Longjiang LI
4
Author Information
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. libo.scu@foxmail.com.
4. 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. muzili63@163.com.
- Publication Type:Research Support, Non-U.S. Gov't
- MeSH:
Humans;
Carcinoma, Squamous Cell/metabolism*;
Cell Proliferation;
DNA, Mitochondrial;
Energy Metabolism;
Glucose;
Mouth Neoplasms/metabolism*;
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism*;
Phosphatidylinositol 3-Kinases;
Reactive Oxygen Species
- From:
International Journal of Oral Science
2023;15(1):37-37
- CountryChina
- Language:English
-
Abstract:
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 PGC1α on OPMDs progression is less unclear. Therefore, we investigated the effects of knockdown PGC1α on 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 PGC1α significantly 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 PGC1α decreased 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 PGC1α plays a crucial role in cell proliferation by reprograming energy metabolism and interfering with energy metabolism, acting as a potential therapeutic target for OPMDs.
