Dominant Negative α-Subunit of FTase Inhibits Effects of Insulin and IGF-I in MCF-7 Cells

• Published in: Biochemical and biophysical research communications Vol. 291; no. 3; pp. 458 - 465
• Main Authors: Solomon, Curtis Scott, Goalstone, Marc Lee
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2002
• Subjects: Akt protein; Alkyl and Aryl Transferases - chemistry; Alkyl and Aryl Transferases - genetics; Alkyl and Aryl Transferases - metabolism; Alkyl and Aryl Transferases - physiology; Breast Neoplasms - enzymology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cell Division; DNA, Neoplasm - biosynthesis; dominant negative α-subunit; farnesyltransferase; Female; geranyl-geranyltransferase; geranylgeranyltransferase I; Humans; insulin; Insulin - pharmacology; Insulin Antagonists - pharmacology; Insulin-Like Growth Factor I - antagonists & inhibitors; MCF-7 cells; Mutation; Phosphorylation; Protein Prenylation; Protein Subunits; Proto-Oncogene Proteins p21(ras) - metabolism; rhoA GTP-Binding Protein - metabolism; Tumor Cells, Cultured; geranylgeranyltransferase I; MCF-7 cells; farnesyltransferase; insulin; dominant negative α-subunit
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.2002.6471

We recently designed a dominant negative (DN) farnesyltransferase (FTase)/geranyl-gerahyltransferase I (GGTase I) α-subunit that when expressed in vascular smooth muscle cells decreased insulin-stimulated phosphorylation of FTase, FTase activity, amounts of farnesylated p21Ras, DNA synthesis, and cell migration. Currently, we explored the inhibitory effects of DN FTase/GGTase I α-subunit in MCF-7 cells on IGF-1- and insulin-stimulated DNA synthesis and cell proliferation. Expression of the DN FTase/GGTase I α-subunit completely blocked IGF-1- and insulin-stimulated BrdU incorporation and cell count. DN FTase/GGTase I α-subunit inhibited insulin-stimulated phosphorylation of FTase/GGTase I α-subunit, FTase and GGTase I activity, and prenylation of p21Ras and RhoA. Expression of DN FTase/GGTase I α-subunit diminished IGF-1- and insulin-stimulated phosphorylation of ERK (extracellular signal-regulated kinase), but had no effect on IGF-1- and insulin-stimulated phosphorylation of Akt. Taken together, these data suggest that DN FTase/GGTase I α-subunit can assuage the mitogenic effects of IGF-1 and insulin on MCF-7 breast cancer cells.