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OBJECTIVE Passage-dependent cel ular senescence is a complex process limiting the proliferative lifespan of tumor cells but the mechanism of this process is not understood.METHODS Replicative senescenceof pancreatic carcinoma-derived PANC-1 cells wasanalyzed.Metabolomics and transcriptomic analyses were performed to find endogenous metabolites changed andassociated genes.Mitochondrial function,cell survival andtumorigenesis of replicative senescent PANC-1 cellswere analyzed.PANC-1 cells were transfected with RNAi CPT1C to specifically knockdown CPT1C expressions,then mitochondrial function,cellular senescence,cell survival and tumorigenesis were investigated.MDA-MB-231,HCT116,A549,MCF7,and He Lacells werealso transfected with si RNA CPT1C and cellular senescence were monitored.RESULTS Replicative senescenceof PANC-1 cells was confirmed.Metabolomic and transcriptomicanalyses revealed that acylcarnitines and their upstream regulator carnitine palmitoyltransferase 1C(CPT1C),an enzyme that catalyzes the initiating step of fatty acidβ-oxidation,were markedly decreased in senescent PANC-1 cells.Furthermore,low CPT1C expression caused abnormal energy metabolism and mitochondrial dysfunction of PANC-1 cells,resulting in decreased cell survival and a suppressed tumorigenesis.Most importantly,loss of CPT1C triggered mitochondrial dysfunction,leading to senescence-like growth suppression and cellular senescence,suppressed cell survival under metabolic stress,and lower tumorigenesis in a mouse xenograft model.Silencing of CPT1C also induced cellular senescence in five other tumor cell lines.CONCLUSION Low CPT1C expression is a novel biomarker and key regulator of cellular senescence in tumor cell lines.Inhibition of CPT1C may be a new cancer therapeutic target impacting cellular senescence and tumorigenesis through modulation of mitochondrial function.
OBJECTIVE Passage-dependent cel ular senescence is a complex process limiting the proliferative lifespan of tumor cells but the mechanism of this process is not understood. METHODS Replicative senescence of pancreatic carcinoma-derived PANC-1 cells wasanalyzed. Metabolomics and transcriptomic analyzes were performed to find endogenous metabolites changed andassociated genes. Mitochondrial function, cell survival and tumorigenesis of replicative senescent PANC-1 cellswere analyzed. PANC-1 cells were transfected with RNAi CPT1C to specifically knockdown CPT1C expressions, then mitochondrial function, cellular senescence, cell survival and tumorigenesis were investigated. MDA -MB-231, HCT116, A549, MCF7, and He Lacells were all transfected with si RNA CPT1C and cellular senescence were monitored. RESULTS Replicative senescence of PANC-1 cells was confirmed. Metabolomic and transcriptomic analysis revealed that acylcarnitines and their upstream regulator carnitine palmitoyltransferase 1C CPT1C), an enzyme that catalyzes the initiating step of fatty acid β-oxidation, were markedly decreased in senescent PANC-1 cells. Frthermore, low CPT1C expression caused abnormal energy metabolism and mitochondrial dysfunction of PANC-1 cells, resulting in decreased cell survival and suppressed tumorigenesis. Most importantly , loss of CPT1C triggered mitochondrial dysfunction, leading to senescence-like growth suppression and cellular senescence, suppressed cell survival under metabolic stress, and lower tumorigenesis in a mouse xenograft model. Silencing of CPT1C also induced cellular senescence in five other tumor cell lines. CONCLUSION Low CPT1C expression is a novel biomarker and key regulator of cellular senescence in tumor cell lines. Inhibition of CPT1C may be a new cancer therapeutic target impacting cellular senescence and tumorigenesis through modulation of mitochondrial function.