Institute of Nutrition, College of Health Care, China Medical University, Taichung 406040, Taiwan.
Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109, United States.
Int J Biol Sci. 2024 May 5;20(8):2790-2813. doi: 10.7150/ijbs.93943. eCollection 2024.
Coenzyme Q (CoQ), a quinone derivative from , has antitumor capabilities. This study investigated the antitumor effect of noncytotoxic CoQ, which included NLRP3 inflammasome inhibition, anti-EMT/metastasis, and metabolic reprogramming via HIF-1α inhibition, in HNSCC cells under normoxia and hypoxia. CoQ suppressed hypoxia-induced ROS-mediated HIF-1α expression in OECM-1 and SAS cells. Under normoxia and hypoxia, the inflammatory NLRP3, ASCcaspase-1, NFκB, and IL-1β expression was reduced by CoQ. CoQ reduced migration/invasion by enhancing epithelial marker E-cadherin and suppressing mesenchymal markers Twist, N-cadherin, Snail, and MMP-9, and MMP-2 expression. CoQ 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, CoQ 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 CoQ 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 CoQ-mediated anti-metastasis (N-Cadherin, Snail, and MMP-9) and metabolic reprogramming (GLUT1, HK-2, and PKM-2) under hypoxia. CoQ 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, CoQ attenuated fibrosis by inhibiting TGF-β and Collagen I expression and suppressed EMT by downregulating Slug and upregulating E-cadherin expression. Interesting, CoQ inhibited the growth of OECM-1 tumors in xenografted mice. Our results advocate CoQ for the therapeutic application against HNSCC.
辅酶 Q（CoQ）是一种来自 的醌衍生物，具有抗肿瘤能力。本研究探讨了非细胞毒性 CoQ 的抗肿瘤作用，包括通过抑制 HIF-1α 抑制 NLRP3 炎性体、抗 EMT/转移和代谢重编程，在常氧和低氧条件下的头颈部鳞状细胞癌（HNSCC）细胞中。CoQ 抑制 OECM-1 和 SAS 细胞中缺氧诱导的 ROS 介导的 HIF-1α 表达。在常氧和低氧条件下，CoQ 降低了炎性 NLRP3、ASC caspase-1、NFκB 和 IL-1β 的表达。CoQ 通过增强上皮标志物 E-钙粘蛋白和抑制间充质标志物 Twist、N-钙粘蛋白、Snail 和 MMP-9、MMP-2 的表达来减少迁移/侵袭。CoQ 抑制葡萄糖摄取、乳酸积累、GLUT1 水平以及参与有氧糖酵解的 HIF-1α 靶基因（HK-2、PFK-1 和 LDH-A）的表达。值得注意的是，CoQ 降低了 OECM-1 细胞的 ECAR 以及糖酵解、糖酵解能力和糖酵解储备，并增强了 OCR、基础呼吸、ATP 生成、最大呼吸和备用能力。使用 LC-ESI-MS 的代谢组学分析表明，CoQ 处理降低了糖酵解中间产物的水平，包括乳酸、2/3-磷酸甘油酸、果糖 1,6-二磷酸和磷酸烯醇丙酮酸，并增加了 TCA 循环代谢产物的水平，包括柠檬酸、异柠檬酸和琥珀酸。在低氧条件下，HIF-1α 沉默逆转了 CoQ 介导的抗转移（N-钙粘蛋白、Snail 和 MMP-9）和代谢重编程（GLUT1、HK-2 和 PKM-2）。CoQ 在常氧和/或低氧条件下阻止了癌症干细胞样特征（上调的 CD24 表达和下调的 CD44、ALDH1 和 OCT4）。此外，在 IL-6 处理的 SG 细胞中，CoQ 通过抑制 TGF-β 和 Collagen I 的表达抑制纤维化，并通过下调 Slug 和上调 E-钙粘蛋白的表达抑制 EMT。有趣的是，CoQ 抑制了异种移植小鼠 OECM-1 肿瘤的生长。我们的研究结果主张将 CoQ 用于治疗头颈部鳞状细胞癌。
