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首页> 外文期刊>Journal of the Formosan Medical Association =: Taiwan yi zhi >Connective tissue growth factor decreases mitochondrial metabolism through ubiquitin-mediated degradation of mitochondrial transcription factor A in oral squamous cell carcinoma
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Connective tissue growth factor decreases mitochondrial metabolism through ubiquitin-mediated degradation of mitochondrial transcription factor A in oral squamous cell carcinoma

机译：结缔组织生长因子通过泛素介导的口腔鳞状细胞癌线粒体转录因子A降解而降低线粒体代谢

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Background/Purpose Deregulation of metabolic pathways is one of the hallmarks of cancer progression. Connective tissue growth factor (CTGF/CCN2) acts as a tumor suppressor in oral squamous cell carcinoma (OSCC). However, the role of CTGF in modulating cancer metabolism is still unclear. Methods OSCC cells stably overexpressing CTGF (SAS/CTGF) and shRNA against CTGF (TW2.6/shCTGF) were established. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were examined by the Seahorse XF24 analyzer. The expression of CTGF and mitochondrial biogenesis related genes was measured by real-time polymerase chain reaction or Western blot analysis. Results CTGF decreased OCR, ECAR, adenosine triphosphate (ATP) generation, mitochondrial DNA (mtDNA), and mitochondrial transcription factor A (mtTFA) protein expression in OSCC cells. Overexpression of mtTFA restored CTGF-decreased OCR, ECAR, mtDNA copy number, migration and invasion of SAS/CTGF cells. Immunoprecipitation assay showed a higher level of ubiquitinated mtTFA protein after CTGF treatment. MG132, an inhibitor of proteasomal degradation, reversed the effect of CTGF on mtTFA protein expression in SAS cells. Conclusion CTGF can decrease glycolysis, mitochondrial oxidative phosphorylation, ATP generation, and mtDNA copy number by increasing mtTFA protein degradation through ubiquitin proteasome pathway and in turn reduces migration and invasion of OSCC cells. Therefore, CTGF may be developed as a potential additive therapeutic drug for oral cancer in the near future.
机译：背景/目的代谢途径的失控是癌症进展的标志之一。结缔组织生长因子（CTGF / CCN2）在口腔鳞状细胞癌（OSCC）中起抑癌作用。但是，CTGF在调节癌症代谢中的作用仍不清楚。方法建立稳定表达CTGF（SAS / CTGF）和shRNA的人CTCC（TW2.6 / shCTGF）的OSCC细胞。用Seahorse XF24分析仪检查耗氧率（OCR）和细胞外酸化率（ECAR）。通过实时聚合酶链反应或蛋白质印迹分析来测量CTGF和线粒体生物发生相关基因的表达。结果CTGF降低了OSCC细胞中的OCR，ECAR，三磷酸腺苷（ATP）生成，线粒体DNA（mtDNA）和线粒体转录因子A（mtTFA）蛋白表达。 mtTFA的过表达恢复了CTGF降低的OCR，ECAR，mtDNA拷贝数，SAS / CTGF细胞的迁移和侵袭。免疫沉淀分析显示CTGF治疗后泛素化的mtTFA蛋白水平更高。蛋白酶体降解抑制剂MG132逆转了CTGF对SAS细胞中mtTFA蛋白表达的影响。结论CTGF可通过泛素蛋白酶体途径增加mtTFA蛋白降解，从而减少糖酵解，线粒体氧化磷酸化，ATP生成和mtDNA拷贝数，进而减少OSCC细胞的迁移和侵袭。因此，CTGF可能在不久的将来发展为潜在的口腔癌治疗药物。

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