辅酶Q0(CoQ0),一种来自樟芝的醌衍生物,具有抗肿瘤能力。这项研究调查了非细胞毒性CoQ0的抗肿瘤作用,其中包括NLRP3炎性体抑制,抗EMT/转移,通过抑制HIF-1α和代谢重编程,在常氧和缺氧下的HNSCC细胞中。CoQ0抑制OECM-1和SAS细胞中缺氧诱导的ROS介导的HIF-1α表达。在常氧和缺氧下,炎性NLRP3,ASC/caspase-1,NFκB,CoQ0降低IL-1β表达。CoQ0通过增强上皮标记E-cadherin和抑制间充质标记Twist减少迁移/侵袭,N-钙黏着蛋白,蜗牛,和MMP-9和MMP-2表达。CoQ0抑制葡萄糖摄取,乳酸积累,GLUT1电平,和参与有氧糖酵解的HIF-1α靶基因(HK-2、PFK-1和LDH-A)表达。值得注意的是,CoQ0减少ECAR以及糖酵解,糖酵解能力,糖酵解储备和增强OCR,基础呼吸,ATP生成,最大呼吸,以及OECM-1电池的备用容量。使用LC-ESI-MS的代谢组学分析显示CoQ0处理降低了糖酵解中间体的水平,包括乳酸,2/3-磷酸甘油酸,果糖1,6-双磷酸酯,和磷酸烯醇丙酮酸,并增加了TCA循环代谢物的水平,包括柠檬酸盐,异柠檬酸,和琥珀酸。HIF-1α沉默逆转CoQ0介导的抗转移(N-Cadherin,蜗牛,和MMP-9)和缺氧下的代谢重编程(GLUT1,HK-2和PKM-2)。CoQ0预防正常氧和/或缺氧下的癌症干细胞样特征(上调的CD24表达和下调的CD44、ALDH1和OCT4)。Further,在IL-6处理的SG细胞中,CoQ0通过抑制TGF-β和胶原蛋白I表达来减轻纤维化,并通过下调Slug和上调E-cadherin表达来抑制EMT。有趣,CoQ0抑制异种移植小鼠中OECM-1肿瘤的生长。我们的结果主张CoQ0用于治疗HNSCC。
Coenzyme Q0 (CoQ0), a quinone derivative from Antrodia camphorata, has antitumor capabilities. This study investigated the antitumor effect of noncytotoxic CoQ0, which included NLRP3 inflammasome inhibition, anti-EMT/metastasis, and metabolic reprogramming via HIF-1α inhibition, in HNSCC cells under normoxia and hypoxia. CoQ0 suppressed hypoxia-induced ROS-mediated HIF-1α expression in OECM-1 and SAS cells. Under normoxia and hypoxia, the inflammatory NLRP3, ASC/caspase-1, NFκB, and IL-1β expression was reduced by CoQ0. CoQ0 reduced migration/invasion by enhancing epithelial marker E-cadherin and suppressing mesenchymal markers Twist, N-cadherin, Snail, and MMP-9, and MMP-2 expression. CoQ0 inhibited glucose uptake, lactate accumulation, GLUT1 levels, and HIF-1α-target gene (HK-2, PFK-1, and LDH-A) expressions that are involved in aerobic glycolysis. Notably, CoQ0 reduced ECAR as well as glycolysis, glycolytic capability, and glycolytic reserve and enhanced OCR, basal respiration, ATP generation, maximal respiration, and spare capacity in OECM-1 cells. Metabolomic analysis using LC-ESI-MS showed that CoQ0 treatment decreased the levels of glycolytic intermediates, including lactate, 2/3-phosphoglycerate, fructose 1,6-bisphosphate, and phosphoenolpyruvate, and increased the levels of TCA cycle metabolites, including citrate, isocitrate, and succinate. HIF-1α silencing reversed CoQ0-mediated anti-metastasis (N-Cadherin, Snail, and MMP-9) and metabolic reprogramming (GLUT1, HK-2, and PKM-2) under hypoxia. CoQ0 prevents cancer stem-like characteristics (upregulated CD24 expression and downregulated CD44, ALDH1, and OCT4) under normoxia and/or hypoxia. Further, in IL-6-treated SG cells, CoQ0 attenuated fibrosis by inhibiting TGF-β and Collagen I expression and suppressed EMT by downregulating Slug and upregulating E-cadherin expression. Interesting, CoQ0 inhibited the growth of OECM-1 tumors in xenografted mice. Our results advocate CoQ0 for the therapeutic application against HNSCC.