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.