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

Yuying Tan, Junjie Li (), Guangyuan Zhao, Kai-Chih Huang, Horacio Cardenas, Yinu Wang, Daniela Matei () and Ji-Xin Cheng ()
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Yuying Tan: Boston University
Junjie Li: Boston University
Guangyuan Zhao: Northwestern University
Kai-Chih Huang: Boston University
Horacio Cardenas: Northwestern University
Yinu Wang: Northwestern University
Daniela Matei: Northwestern University
Ji-Xin Cheng: Boston University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32101-w

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