Lipotoxicity, caused by intracellular
lipid accumulation, accelerates the degenerative process of cellular senescence, which has implications in
cancer development and
therapy. Previously,
carnitine palmitoyltransferase 1C (CPT1C), a mitochondrial
enzyme that catalyzes carnitinylation of
fatty acids, was found to be a critical regulator of
cancer cell senescence. However, whether loss of CPT1C could induce senescence as a result of lipotoxicity remains unknown. An LC/MS-based lipidomic analysis of PANC-1, MDA-MB-231, HCT-116 and A549
cancer cells was conducted after
siRNA depletion of CPT1C. Cellular lipotoxicity was further confirmed by lipotoxicity assays. Significant changes were found in the lipidome of CPT1C-depleted cells, including major alterations in
fatty acid,
diacylglycerol,
triacylglycerol, oxidative
lipids,
cardiolipin,
phosphatidylglycerol,
phosphatidylcholine/
phosphatidylethanolamine ratio and
sphingomyelin. This was coincident with changes in expressions of mRNAs involved in lipogenesis. Histological and biochemical analyses revealed higher
lipid accumulation and increased
malondialdehyde and
reactive oxygen species, signatures of lipid peroxidation and oxidative stress. Reduction of
ATP synthesis, loss of mitochondrial transmembrane potential and down-regulation of expression of mitochondriogenesis gene mRNAs indicated
mitochondrial dysfunction induced by lipotoxicity, which could further result in cellular senescence. Taken together, this study demonstrated CPT1C plays a critical role in the regulation of
cancer cell lipotoxicity and cell senescence, suggesting that inhibition of CPT1C may serve as a new therapeutic strategy through induction of
tumor lipotoxicity and senescence.