New tricks for human farnesyltransferase inhibitor: cancer and beyond

Abstract

Human protein farnesyltransferase (FTase) catalyzes the addition of a C₁₅-farnesyl lipid group to the cysteine residue located in the COOH-terminal tetrapeptide motif of a variety of important substrate proteins, including well-known Ras protein superfamily. The farnesylation of Ras protein is required both for its normal physiological function, and for the transforming capacity of its oncogenic mutants. Over the last several decades, FTase inhibitors (FTIs) were developed to disrupt the farnesylation of oncogenic Ras as anti-cancer agents, and some of them have entered cancer clinical investigation. On the other hand, some substrates of FTase were demonstrated to be related with other human diseases, including Hutchinson-Gilford progeria syndrome, chronic hepatitis D, and cardiovascular diseases. In this review, we summarize the roles of FTase in malignant transformation, proliferation, apoptosis, angiogenesis, and metastasis of tumor cells, and the recently anticancer clinical research advances of FTIs. The therapeutic prospect of FTIs on several other human diseases is also discussed.

Fig. 1. The farnesylation modification of Ras protein. FTase links a 15-carbon farnesyl isoprenoid lipid to cysteine of the CAAX motif, and enable the proteins insert into the ER. Then the AAX amino acids of Ras are removed on ER by RCE1, and a carboxymethyl is attached to the terminal cysteine by ICMT. Finally, palmitoyltransferase catalyzes the addition of two palmitoyl long-chain fatty acid groups to the upstream cysteine of the farnesylated carboxyterminal cysteine to obtain a hydrophobic tail that has affinity for membranes.

Fig. 2. FTIs mentioned in this review. *The structure of PD169541 (12) is unavailable.

Fig. 3. The versatile roles of FTase targets in tumor. The FTase substrate, Ras, can promote cancer development by suppressing apoptosis, inducing angiogenesis, accelerating metastasis and altering cell cycle, through PI3K-Akt, Raf-MAPK-MEK and other signaling pathways. Meanwhile, other FTase substrates, including RhoB, Rheb, Rac1, Spindly, CENP-E and CENP-F, are also involved in the regulation of apoptosis and cell cycle in tumor cells.

Fig. 4. Roles of FTIs in HGPS and chronic hepatitis D. In HGPS cells, inhibition of FTase blocks the farnesylation of the mutant prelamin A, progerin, which subsequently target to the nuclear rim to cause misshapen nuclei. In chronic hepatitis D, inhibition of FTase suppresses the prenylation of large hepatitis delta antigen (LHDAg) thereby prevents its formation of virus-like particles (VLPs) with the HBV surface antigen (HBsAg) in HBV-infected cells, which then secret and increase infection.

Fig. 5. Roles of FTIs in cardiovascular diseases. a) FTIs are effective in slowing the accelerated progression of atherosclerosis and vascular calcification since it leads to a decrease in oxidative stress and inflammation via both systemic and direct local effects on the vessel wall. b) FTIs may inhibit VSMC mineralization in vascular calcification by activating downstream PI3K-Akt signaling and preventing apoptosis of VSMC. c) FTIs may inhibit neovascularization in atherosclerosis via disturbing their motility by significantly impairing centrosome reorientation toward their leading edge and interrupting the interaction between FTase and the cytoskeletal protein.