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The role and therapeutic implication of CPTs in fatty acid oxidation and cancers progression.

ABSTRACT: Cancer cells must maintain metabolic homeostasis under a wide range of conditions and meet their own energy needs in order to survive and reproduce. In addition to glycolysis, cancer cells can also perform various metabolic strategies, such as fatty acid oxidation (FAO). It has been found that the proliferation, survival, drug resistance and metastasis of cancer cells depend on FAO. The carnitine palmitoyltransferase (CPT), including CPT1 and CPT2, located on the mitochondrial membrane, are important mediators of FAO. In recent years, many researchers have found that CPT has a close relationship with the metabolic development of tumor cells, not only provides energy for cancer cells development and metastasis by promoting FAO but also affects the occurrence and invasion through other signal pathways or cytokines or microRNA. This review summarized the role of CPTs in several kinds of tumors and the developed targeted inhibitors of CPTs, as well as the potential gene therapy and immunotherapy of CPTs, hoping to better explore the mechanism and role of CPTs in the future and providing useful ideas for clinical treatment.

SUBMITTER: Wang J

PROVIDER: S-EPMC8263643 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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The role and therapeutic implication of CPTs in fatty acid oxidation and cancers progression.

Wang Junmin J Xiang Hongjiao H Lu Yifei Y Wu Tao T Ji Guang G

American journal of cancer research 20210615 6

Cancer cells must maintain metabolic homeostasis under a wide range of conditions and meet their own energy needs in order to survive and reproduce. In addition to glycolysis, cancer cells can also perform various metabolic strategies, such as fatty acid oxidation (FAO). It has been found that the proliferation, survival, drug resistance and metastasis of cancer cells depend on FAO. The carnitine palmitoyltransferase (CPT), including CPT1 and CPT2, located on the mitochondrial membrane, are impo ...[more]

PMID: 34249411

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Project description:Right ventricular hypertrophy (RVH) and RV failure are major determinants of prognosis in pulmonary hypertension and congenital heart disease. In RVH, there is a metabolic shift from glucose oxidation (GO) to glycolysis. Directly increasing GO improves RV function, demonstrating the susceptibility of RVH to metabolic intervention. However, the effects of RVH on fatty acid oxidation (FAO), the main energy source in adult myocardium, are unknown. We hypothesized that partial inhibitors of FAO (pFOXi) would indirectly increase GO and improve RV function by exploiting the reciprocal relationship between FAO and GO (Randle's cycle). RVH was induced in adult Sprague-Dawley rats by pulmonary artery banding (PAB). pFOXi were administered orally to prevent (trimetazidine, 0.7 g/L for 8 weeks) or regress (ranolazine 20 mg/day or trimetazidine for 1 week, beginning 3 weeks post-PAB) RVH. Metabolic, hemodynamic, molecular, electrophysiologic, and functional comparisons with sham rats were performed 4 or 8 weeks post-PAB. Metabolism was quantified in RV working hearts, using a dual-isotope technique, and in isolated RV myocytes, using a Seahorse Analyzer. PAB-induced RVH did not cause death but reduced cardiac output and treadmill walking distance and elevated plasma epinephrine levels. Increased RV FAO in PAB was accompanied by increased carnitine palmitoyltransferase expression; conversely, GO and pyruvate dehydrogenase (PDH) activity were decreased. pFOXi decreased FAO and restored PDH activity and GO in PAB, thereby increasing ATP levels. pFOXi reduced the elevated RV glycogen levels in RVH. Trimetazidine and ranolazine increased cardiac output and exercise capacity and attenuated exertional lactic acidemia in PAB. RV monophasic action potential duration and QTc interval prolongation in RVH normalized with trimetazidine. pFOXi also decreased the mild RV fibrosis seen in PAB. Maladaptive increases in FAO reduce RV function in PAB-induced RVH. pFOXi inhibit FAO, which increases GO and enhances RV function. Trimetazidine and ranolazine have therapeutic potential in RVH.

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The role and therapeutic implication of CPTs in fatty acid oxidation and cancers progression.

Publications

The role and therapeutic implication of CPTs in fatty acid oxidation and cancers progression.

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