敲低PGC1α通过重编程能量代谢抑制口腔角化细胞增殖。

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE International Journal of Oral Science Pub Date : 2023-09-04 DOI:10.1038/s41368-023-00242-3
Yunkun Liu, Nengwen Huang, Xianghe Qiao, Zhiyu Gu, Yongzhi Wu, Jinjin Li, Chengzhou Wu, Bo Li, Longjiang Li
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引用次数: 1

摘要

口腔潜在恶性疾病(OPMDs)是口腔鳞状细胞癌(OSCC)的前体。细胞能量代谢失调是癌细胞的一个重要标志。过氧化物酶体增殖体激活受体- γ辅激活因子-1 α (PGC1α)在线粒体能量代谢中起重要作用。然而,PGC1α在OPMDs进展中的分子机制尚不清楚。因此,我们从细胞增殖、细胞周期、细胞凋亡、异种移植肿瘤、线粒体DNA (mtDNA)、线粒体电子传递链复合物(ETC)、活性氧(ROS)、氧耗率(OCR)、细胞外酸化率(ECAR)和葡萄糖摄取等方面全面研究了PGC1α下调对人口腔角化不良细胞(DOKs)的影响。我们发现,敲低PGC1α可显著抑制DOKs体外增殖和体内肿瘤生长,诱导s期阻滞,抑制PI3K/Akt信号通路,但不影响细胞凋亡。机制上,PGC1α下调可降低mtDNA、ETC和OCR,同时通过调节乳酸脱氢酶A (LDHA)增强ROS、葡萄糖摄取、ECAR和糖酵解。此外,SR18292(一种PGC1α抑制剂)诱导DOKs氧化磷酸化功能障碍,并减缓DOK异种移植肿瘤的进展。因此,我们的研究表明,PGC1α通过重编程能量代谢和干扰能量代谢,在细胞增殖中起着至关重要的作用,是OPMDs的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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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 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.

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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
期刊最新文献
Organoids in the oral and maxillofacial region: present and future. Personalized bioceramic grafts for craniomaxillofacial bone regeneration An unexpected role of neurite outgrowth inhibitor A as regulator of tooth enamel formation Periodontitis impacts on thrombotic diseases: from clinical aspect to future therapeutic approaches. CREB3L1 deficiency impairs odontoblastic differentiation and molar dentin deposition partially through the TMEM30B.
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