Metabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation in platinum-resistant cancer cells

• Published in: Nature communications 2022-08, Vol.13 (1), p.4554-16, Article 4554
• Main Authors: Tan, Yuying, Li, Junjie, Zhao, Guangyuan, Huang, Kai-Chih, Cardenas, Horacio, Wang, Yinu, Matei, Daniela, Cheng, Ji-Xin
• Format: Article
• Language: English
• Subjects: 14/19; 14/34; 140/133; 38; 38/109; 45/77; 631/1647/245/2226; 631/67/1059/2326; 631/67/2327; 64/60; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cancer; Carboplatin; Cell Line, Tumor; Cell survival; Chemoresistance; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; Drug Resistance, Neoplasm; Energy metabolism; Fatty acids; Fatty Acids - pharmacology; Female; Glucose; Glucose - metabolism; Glycolysis; Humanities and Social Sciences; Humans; In vivo methods and tests; Lipogenesis; Metabolism; multidisciplinary; Ovarian cancer; Ovarian Neoplasms - pathology; Oxidation; Oxidation resistance; Oxidative stress; Platinum; Platinum - pharmacology; Raman spectra; Science; Science (multidisciplinary); Tumor cell lines; Tumors; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32101-w

Increased glycolysis is considered as a hallmark of cancer. Yet, cancer cell metabolic reprograming during therapeutic resistance development is under-studied. Here, through high-throughput stimulated Raman scattering imaging and single cell analysis, we find that cisplatin-resistant cells exhibit increased fatty acids (FA) uptake, accompanied by decreased glucose uptake and lipogenesis, indicating reprogramming from glucose to FA dependent anabolic and energy metabolism. A metabolic index incorporating glucose derived anabolism and FA uptake correlates linearly to the level of cisplatin resistance in ovarian cancer (OC) cell lines and primary cells. The increased FA uptake facilitates cancer cell survival under cisplatin-induced oxidative stress by enhancing beta-oxidation. Consequently, blocking beta-oxidation by a small molecule inhibitor combined with cisplatin or carboplatin synergistically suppresses OC proliferation in vitro and growth of patient-derived xenografts in vivo. Collectively, these findings support a rapid detection method of cisplatin-resistance at single cell level and a strategy for treating cisplatin-resistant tumors. Metabolic reprogramming is associated with cancer initiation, progression and resistance to therapy. Here, the authors show that metabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation is associated with cancer-cell platinum-based chemotherapy resistance.