Effects of carnitine palmitoyltransferases on cancer cellular senescence

Abstract

The carnitine palmitoyltransferase (CPT) family is essential for fatty acid oxidation. Recently, we found that CPT1C, one of the CPT1 isoforms, plays a vital role in cancer cellular senescence. However, it is unclear whether other isoforms (CPT1A, CPT1B, and CPT2) have the same effect on cellular senescence. This study illustrates the different effects of CPT knockdown on PANC-1 cell proliferation and senescence and MDA-MB-231 cell proliferation and senescence, as demonstrated by cell cycle kinetics, Bromodeoxyuridine incorporation, senescence-associated β-galactosidase activity, colony formation, and messenger RNA (mRNA) expression of key senescence-associated secretory phenotype factors. CPT1C exhibits the most substantial effect on cell senescence. Lipidomics analysis was performed to further reveal that the knockdown of CPTs changed the contents of lipids involved in mitochondrial function, and lipid accumulation was induced. Moreover, the different effects of the isoform deficiencies on mitochondrial function were measured and compared by the level of radical oxygen species, mitochondrial transmembrane potential, and the respiratory capacity, and the expression of the genes involved in mitochondrial function were determined at the mRNA level. In summary, CPT1C exerts the most significant effect on mitochondrial dysfunction-associated tumor cellular senescence among the members of the CPT family, which further supports the crucial role of CPT1C in cellular senescence and suggests that inhibition of CPT1C may represent as a new strategy for cancer treatment through the induction of tumor senescence.

Signaling, metabolism, and cancer: An important relationship for therapeutic intervention

“…In previous sections, we mentioned the importance of oxidation of fatty acids and increased expression of CPTC1 in cancer cells. Recently, it has been shown that inhibition of CPTC1 causes increased senescence of cancer cells, and can be considered as a new therapy approach for treatment of cancer (Guan et al, 2019). Some studies have also focused on the metabolism of amino acids for treatment of cancer.…”

Carnitine palmitoyltransferase 1C contributes to progressive cellular senescence

“…CPT1C, an enzyme located in the outer mitochondrial membrane [32], is involved in lipid metabolism, cellular energy supply [33][34][35] and other physiological or pathological processes [36][37][38][39]. The knockdown of CPT1C inhibited the tumorigenesis of PANC-1 cells in vivo [2,33] and further suppressed xenograft tumor growth in situ [2], suggesting that CPT1C represents a therapeutic target for cancer treatment.…”

Carnitine palmitoyltransferase 1C reverses cellular senescence of MRC‐5 fibroblasts via regulating lipid accumulation and mitochondrial function

“…Mitochondrial respiration was evaluated by the OCR with a Seahorse XF-96 Extracellular Flux Analyzer (Seahorse Bioscience) as described previously (Guan et al, 2019;Wang et al, 2018). Briefly, 2 × 10 4 cells were seeded in XF-96 cell culture plates (Seahorse Bioscience) overnight and the medium was replaced with XF assay medium (Seahorse Bioscience) the next day.…”

“…It has been reported that CPT1C promotes tumor cell and stem cell survival under metabolic stress conditions (Roa‐Mansergas et al, 2018; Wang et al, 2017; Zaugg et al, 2011). Most recently, we found that CPT1C is a key regulator of tumor cell proliferation and senescence (Chen et al, 2017; Wang et al, 2018), exerting the most prominent role in mitochondrial dysfunction‐associated cellular senescence compared with other subtypes (Guan et al, 2019).…”