J Biomed Transl Res.  2017 Sep;18(3):113-117. 10.12729/jbtr.2017.18.3.113.

Adverse effects of farnesyltransferase inhibitors on insulin actions

• Yi SJ
• Jhun BH
• Kim K

• KMID: 2394597
• DOI: http://doi.org/10.12729/jbtr.2017.18.3.113

Abstract

Ras activates a series of downstream effectors, including the mitogen-activated protein kinase pathway and the Rac/Rho pathway after insulin stimulation. Mutations in Ras are found in approximately 30% of all human cancers and are critical factors in tumor initiation and maintenance. There are four Ras proteins with 80-90% amino acid sequence homology with major differences in the carboxyl termini. Ras proteins undergo farnesylation on their carboxyl termini catalyzed by the enzyme protein farnesyltransferase (FTase), which facilitates localization of Ras proteins to the inner surface of the plasma membrane. Because inhibition of FTase would prevent Ras from processing into its active form, FTase is viewed as a potential therapeutic target. A variety of FTase inhibitors have showed great potency against tumor cells in preclinical studies. Although many farnesyltransferase inhibitors have been developed, their adverse effects on the mitogenic and metabolic actions of insulin are not completely understood. Here we show that YH3096, a farnesyltransferase inhibitor, inhibits insulin-mediated DNA synthesis in HIRc-B cells without affecting c-Jun expression and membrane ruffling in HIRc-B cells. Moreover, YH3096 and its derivatives did not affect insulin-induced glucose uptake in 3T3-L1 adipocytes. Our results provide a laboratory evaluation of the effects of Ras inhibitors on insulin functions.

Keyword

Ras; farnesyltransferase inhibitor; YH3096; insulin; DNA synthesis

MeSH Terms

Adipocytes
Cell Membrane
DNA
Farnesyltranstransferase*
Glucose
Humans
Insulin*
Membranes
Prenylation
Protein Kinases
ras Proteins
Sequence Homology, Amino Acid
DNA
Farnesyltranstransferase
Glucose
Insulin
Protein Kinases
ras Proteins