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Int J Biol Sci 2024; 20(8):2790-2813. doi:10.7150/ijbs.93943 This issue Cite

Research Paper

Coenzyme Q₀ inhibited the NLRP3 inflammasome, metastasis/EMT, and Warburg effect by suppressing hypoxia-induced HIF-1α expression in HNSCC cells

Hsin-Ling Yang^1,#, Che-Wei Chang¹, Chithravel Vadivalagan^2,#, Sudhir Pandey³, Siang-Jyun Chen¹, Chuan-Chen Lee⁴, Jhih-Hsuan Hseu^5,✉, You-Cheng Hseu^3,4,6,7,✉

1. Institute of Nutrition, College of Health Care, China Medical University, Taichung 406040, Taiwan.
2. Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109, United States.
3. Department of Cosmeceutics, College of Pharmacy, China Medical University, Taichung 406040, Taiwan.
4. Department of Health and Nutrition Biotechnology, Asia University, Taichung 413305, Taiwan.
5. Department of Dermatology, Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
6. Chinese Medicine Research Center, China Medical University, Taichung 404333, Taiwan.
7. Research Center of Chinese Herbal Medicine, China Medical University, Taichung 404333, Taiwan.
^#Equal contribution.

✉ Corresponding authors: Dr. You-Cheng Hseu, Professor, Department of Cosmeceutics, College of Pharmacy, China Medical University, Shui-Nan Campus, No. 100, Sec. 1, Jingmao Road, Taichung 406040, Taiwan. Phone: +886-4 22053366-7503; Fax: +886-4 2207 8083; E-mail address: ychseucmu.edu.tw. Dr. Jhih-Hsuan Hseu, Department of Dermatology, Chang Gung Memorial Hospital, No. 123, Dapi Road, Niaosong District, Kaohsiung 83301, Taiwan. Tel.: 886-4-2205-3366 ext 7503; Fax: 886-4-22062891; E-mail: shirleyshirley19970311com. More

Abstract

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.

Keywords: CoQ₀, HIF-1α, NLRP3, EMT, Warburg effect

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