NEW THERAPEUTIC POTENTIAL OF LOW-DOSE FARNESYLTRANSFERASE INHIBITORS IN ATHEROSCLEROSIS, SEVERE INFECTION, MAJOR TRAUMA, FULMINANT HEPATITIS AND OBESITY

Masao Kaneki

Department of Anesthesia, Critica Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, USA

Abstract

Protein farnesylation is a lipid modification of the cysteine residues in the CAAX motif located in the carboxyl terminus of proteins (“C” is cysteine, “A” is aliphatic amino acid, and “X” is any amino acid at the carboxyl terminus, but usually serine, methionine, glutamine, or alanine). Farnesyltransferase (FTase) inhibitors (FTIs) have been developed as anti-cancer/leukemia drugs and clinical trials have been conducted in patients with cancer or hematologic malignancies and in progeria syndrome. It has been proposed that inhibition of protein farnesylation is a mediator of the cholesterol-lowering-independent beneficial effects of statins, inhibitors of HMG-CoA reductase, albeit direct evidence is lacking. We have shown that low-dose FTIs effectively prevents atherosclerosis development in apoE-deficient mice on high-fat diet without decreasing circulating cholesterol levels, improves survival in mouse models of sepsis and fulminant hepatitis, and reverses insulin resistance and metabolic aberration after burn injury in mice. Of note, FTIs exerts anti-inflammatory effects while concomitantly increasing bactericidal activities of immune cells, indicative that FTIs are not a simple anti-inflammatory agent. Moreover, our recent study showed that low-dose FTI inhibited high-fat high-sucrose diet-induced obesity and diabetes in mice, whereas FTI did not decrease body weight in mice on normal chow. The classical targets of FTIs are Ras and Rheb in cancer and leukemia and lamin A in progeria syndrome. These proteins are constitutively farnesylated and farnesylation is the first step of protein maturation that is followed by further processing (such as methylation and cleavage at the site of farnesylated cysteines). In contrast, we have found that there exists inducible farnesylation where proteins get farnesylated under certain conditions such as inflammation, whereas those proteins are not farnesylated or farnesylated to a small extent under normal conditions. Collectively, our data identify inducible farnesylation as a novel molecular target to prevent and/or treat a broad array of human diseases where inflammatory response plays a critical role.

Keywords: Therapeutic agent, inflammation, farnesylation inhibitor

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