Carnitine palmitoyltransferase 1C contributes to progressive cellular senescence

Abstract

Stable transfection manipulation with antibiotic selection and passaging induces progressive cellular senescence phenotypes. However, the underlying mechanisms remain poorly understood. This study demonstrated that stable transfection of the empty vector induced PANC-1 cells into cellular senescence. Metabolomics revealed several acylcarnitines and their upstream regulatory gene, carnitine palmitoyltransferase 1C (CPT1C) involved in fatty acid β-oxidation in mitochondria, were strikingly decreased in senescent PANC-1 cells. Low CPT1C expression triggered mitochondrial dysfunction, inhibited telomere elongation, impaired cell survival under metabolic stress, and hindered the malignance and tumorigenesis of senescent cells. On the contrary, mitochondrial activity was restored by CPT1C gain-of-function in senescent vector PANC-1 cells. PPARα and TP53/CDKN1A, crucial signaling components in cellular senescence, were downregulated in senescent PANC-1 cells. This study identifies CPT1C as a key regulator of stable transfection-induced progressive PANC-1 cell senescence that inhibits mitochondrial function-associated metabolic reprogramming. These findings confirm the need to identify cell culture alterations after stable transfection, particularly when cells are used for metabolomics and mitochondria-associated studies, and suggest inhibition of CPT1C could be a promising target to intervene pancreatic tumorigenesis.

Lipid metabolism in pancreatic cancer: emerging roles and potential targets

“…Besides, the knockdown of CPT1C inhibited the growth and tumorigenesis of PC [198]. Regarding the role of cell death related to lipid catabolism, targeting ferroptosis may be another attractive treatment for cancer.…”

“…At the molecular level, it has been observed that CPT1A and CPT1B levels are higher in drug‐resistant pancreatic CSCs, and the oxidative phosphorylation in drug‐resistant cells was due to FAO [ 195 ]. Knockdown of CPT1C inhibited the tumorigenesis of PANC‐1 cells in vivo and further suppressed xenograft tumor growth in situ [ 198 ]. In conclusion, the dynamic FAO regulation exerts a critical role in cancer progression, and targeting the FAO signaling pathway might be a promising therapeutic strategy for PC.…”

Metformin Attenuates UVA-Induced Skin Photoaging by Suppressing Mitophagy and the PI3K/AKT/mTOR Pathway

“…Mitophagy is activated in senescent cells [36]. Mitochondrial depolarization is a hallmark of mitophagy [37].…”

MicroRNA-Regulated Signaling Pathways: Potential Biomarkers for Pancreatic Ductal Adenocarcinoma

“…The involvement of carnitine palmitoyltransferase 1C (CPT1C) in the mitochondrial β-oxidation of fatty acids is important for cell survival. Low activity of CPT1C results in a negative cellular outcome with increased metabolic and oxidative stress, decreased cell growth, and dysregulated mitochondria [157]. Increasing the expression and activity of CPT1C reverses the negative cellular effects.…”