Cellular senescence is a fundamental biological process that has profound implications in cancer development and therapeutics, but the underlying mechanisms remain elusive. Here we show that carnitine palmitoyltransferase 1C (CPT1C), an enzyme that catalyzes carnitinylation of fatty acids for transport into mitochondria for β-oxidation, plays a major role in the regulation of cancer cell senescence through mitochondria-associated metabolic reprograming. Metabolomics analysis suggested alterations in mitochondria activity, as revealed by the marked decrease in acylcarnitines in senescent human pancreatic carcinoma PANC-1 cells, indicating low CPT1C activity. Direct analyses of mRNA and protein show that CPT1C is significantly reduced in senescent cells. Furthermore, abnormal mitochondrial function was observed in senescent PANC-1 cells, leading to lower cell survival under metabolic stress and suppressed tumorigenesis in a mouse xenograft model. Knock-down of CPT1C in PANC-1 cells induced mitochondrial dysfunction, caused senescence-like growth suppression and cellular senescence, suppressed cell survival under metabolic stress, and inhibited tumorigenesis in vivo. Further, CPT1C knock-down suppressed xenograft tumor growth in situ. Silencing of CPT1C in five other tumor cell lines also caused cellular senescence. On the contrary, gain-of-function of CPT1C reversed PANC-1 cell senescence and enhanced mitochondrial function. This study identifies CPT1C as a novel biomarker and key regulator of cancer cell senescence through mitochondria-associated metabolic reprograming, and suggests that inhibition of CPT1C may represent a new therapeutic strategy for cancer treatment through induction of tumor senescence.
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The authors are grateful to Drs. Jun Du, Xiaoyan Shen, and Jun Li from Sun Yat-sen University for generously providing various cell lines. This study was supported by the Natural Science Foundation of China (Grants: 81522047, 81573489, 81373470, 81320108027), the 111 Project (Grant: B16047), the Key Laboratory Foundation of Guangdong Province (Grant: 2011A060901014), and the Guangzhou Health Care Collaborative Innovation Program (Grant: 201508020250).
HB, MH, PH and YW designed the experiments, YW, YC, LG, HZ and YH conducted the experiments, YW and HB performed data analysis, YW, HB, FJG, CHJ, AY, and PH wrote the paper, ZW, SY, YW, PC and XF contributed to new reagents or analytical tools.