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Knockdown of PGC1α suppresses dysplastic oral keratinocytes proliferation through reprogramming energy metabolism
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 met...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10475463/ https://www.ncbi.nlm.nih.gov/pubmed/37661238 http://dx.doi.org/10.1038/s41368-023-00242-3 |
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author | Liu, Yunkun Huang, Nengwen Qiao, Xianghe Gu, Zhiyu Wu, Yongzhi Li, Jinjin Wu, Chengzhou Li, Bo Li, Longjiang |
author_facet | Liu, Yunkun Huang, Nengwen Qiao, Xianghe Gu, Zhiyu Wu, Yongzhi Li, Jinjin Wu, Chengzhou Li, Bo Li, Longjiang |
author_sort | Liu, Yunkun |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10475463 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-104754632023-09-05 Knockdown of PGC1α suppresses dysplastic oral keratinocytes proliferation through reprogramming energy metabolism Liu, Yunkun Huang, Nengwen Qiao, Xianghe Gu, Zhiyu Wu, Yongzhi Li, Jinjin Wu, Chengzhou Li, Bo Li, Longjiang Int J Oral Sci Article 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. Nature Publishing Group UK 2023-09-04 /pmc/articles/PMC10475463/ /pubmed/37661238 http://dx.doi.org/10.1038/s41368-023-00242-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Liu, Yunkun Huang, Nengwen Qiao, Xianghe Gu, Zhiyu Wu, Yongzhi Li, Jinjin Wu, Chengzhou Li, Bo Li, Longjiang Knockdown of PGC1α suppresses dysplastic oral keratinocytes proliferation through reprogramming energy metabolism |
title | Knockdown of PGC1α suppresses dysplastic oral keratinocytes proliferation through reprogramming energy metabolism |
title_full | Knockdown of PGC1α suppresses dysplastic oral keratinocytes proliferation through reprogramming energy metabolism |
title_fullStr | Knockdown of PGC1α suppresses dysplastic oral keratinocytes proliferation through reprogramming energy metabolism |
title_full_unstemmed | Knockdown of PGC1α suppresses dysplastic oral keratinocytes proliferation through reprogramming energy metabolism |
title_short | Knockdown of PGC1α suppresses dysplastic oral keratinocytes proliferation through reprogramming energy metabolism |
title_sort | knockdown of pgc1α suppresses dysplastic oral keratinocytes proliferation through reprogramming energy metabolism |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10475463/ https://www.ncbi.nlm.nih.gov/pubmed/37661238 http://dx.doi.org/10.1038/s41368-023-00242-3 |
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