Genetics and molecular biology: fatty acid metabolism in cancer cell survival; carnitine palmitoyltransferase-1 as a critical anticancer target

Cancer cells can be killed by reducing the production of ATP from various pathways, however, this has not been exploited to any great extent in cancer therapy, principally because orthodox cytotoxic compounds were either effective in killing cells or resulted in multidrug resistance. An upregulation of the fatty acid synthase gene (FASN) has been observed in many cancer cells and indeed the overexpression of FASN in human mammary epithelial cells following transient transfection with a full length FASN plasmid appears to be sufficient to progress the cells toward a neoplastic state. It would appear that the overproduction of fatty acids is favourable toward the progression and survival of cancer cells. Human breast cancer cells could be effectively killed by the simultaneous inhibition of fatty acid transport to the mitochondria for beta-oxidation via carnitine palmitoyl transferase-1 (CPT-1) which is regulated by the CPT1C gene. In retrospect this is an extremely important pathway as beta-oxidation is the most efficient cellular ATP-generating system. The CPT1C gene correlates closely with tumour cell survival and human lung tumours overexpress the CPT1C gene with the level of overexpression being between 10- and 100-fold greater. In MCF-7 human breast cancer cells CPT1C was overexpressed and in comparison to cells which had been transfected with control vector, fatty acid oxidation (palmitic acid) and ATP production were increased. It has also been shown that the CPT1C gene confers resistance to rapamycin. It was demonstrated that HT116 human colon cancer cells could be sensitised toward rapamycin-induced inhibition of growth by siRNA targeted at the CPT1C gene. This clearly reveals the critical importance of CPT1C gene expression in cancer cell survival. This has been confirmed by the demonstration that the growth of human breast cancer cells correlates with increased expression of the CPT1C gene and inhibition of CPT-1 activity (by etomoxir - a CPT-1 inhibitor) resulted in a pronounced reduction in the viability of human glioblastoma cells. This is important as glioblastoma cells are intensely resistant to cell death mechanisms and thus affirms CPT-1 and its expression as an important anticancer target.