Fatty acid oxidation and carnitine palmitoyltransferase I: emerging therapeutic targets in cancer

Abstract

Tumor cells exhibit unique metabolic adaptations that are increasingly viewed as potential targets for novel and specific cancer therapies. Among these targets, the carnitine palmitoyltransferase system is responsible for delivering the long-chain fatty acid (FA) from cytoplasm into mitochondria for oxidation, where carnitine palmitoyltransferase I (CPTI) catalyzes the rate-limiting step of fatty acid oxidation (FAO). With increasing understanding of the crucial role had by fatty acid oxidation in cancer, CPTI has received renewed attention as a pivotal mediator in cancer metabolic mechanism. CPTI activates FAO and fuels cancer growth via ATP and NADPH production, constituting an essential part of cancer metabolism adaptation. Moreover, CPTI also functionally intertwines with other key pathways and factors to regulate gene expression and apoptosis of cancer cell. Here, we summarize recent findings and update the current understanding of FAO and CPTI in cancer and provide theoretical basis for this enzyme as an emerging potential molecular target in cancer therapeutic intervention.

A new role for extracellular vesicles: how small vesicles can feed tumors' big appetite

“…The key role of FAO in cancer cell metabolism has recently emerged (68,69). This catabolic process is upregulated in numerous tumors.…”

“…This catabolic process is upregulated in numerous tumors. Particularly, the expression of carnitine palmitoyl transferase 1 (CPT1), the rate-limiting enzyme involved in FA transport from the cytosol to the mitochondria, is increased in tumor cells and, in many models, CPT1 inhibition has an antitumor effect (69). Increased FAO in tumors drives cell proliferation (70) and survival, by preventing loss of attachment-induced anoikis (71), both of which depend on ATP production.…”

Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis

“…This acetyl-CoA then enters the mitochondrial tricarboxylic acid (TCA) cycle to generate energy. The NADH and FADH 2 produced by both FA b-oxidation and the TCA cycle are also used by the electron transport chain to produce ATP as an energy source (Eaton et al, 2001;Qu et al, 2016).…”

“…After entering the cell, a CoA group is added to the FA by fatty acyl-CoA synthase (FACS) to form a longchain acyl-CoA. Carnitine palmitoyltransferase 1 (CPT1) is a longchain FA transport protein rate-limiting for b-oxidation and it converts the long-chain acyl-CoA to long-chain acylcarnitine, thus allowing the modified FA to be transported across the inner mitochondrial membrane by carnitine translocase (CAT), which exchanges long-chain acylcarnitines for carnitine (Eaton et al, 2001;Qu et al, 2016). The inner mitochondrial membrane located CPT2 then reverts the long-chain acylcarnitine back to long-chain acylCoA for it to be fed into the FA b-oxidation pathway, which results in the production of one acetyl-CoA from each cycle of FA boxidation.…”

New Developments of Gastric Cancer Biomarker Research

“…Few researches studied the fatty acid metabolism metabolites in gastric cancer patients. However, both increased fatty acid synthesis (FASN) and increased fatty acid oxidation (CPT1A) have been associated with cancer development [65][66][67]. Fatty acid oxidation metabolites such as acetone and β-hydroxybutyrate have been identified as potential biomarkers of gastric cancer [68,69].…”