Dominant negative alpha-subunit of FTase inhibits effects of insulin and IGF-I in MCF-7 cells.
We recently designed a dominant negative (DN) farnesyltransferase (FTase)/geranyl-gerahyltransferase I (GGTase I) alpha-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 alpha-subunit in MCF-7 cells on IGF-1- and insulin-stimulated DNA synthesis and cell proliferation. Expression of the DN FTase/GGTase I alpha-subunit completely blocked IGF-1- and insulin-stimulated BrdU incorporation and cell count. DN FTase/GGTase I alpha-subunit inhibited insulin-stimulated phosphorylation of FTase/GGTase I alpha-subunit, FTase and GGTase I activity, and prenylation of p21Ras and RhoA. Expression of DN FTase/GGTase I alpha-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 alpha-subunit can assuage the mitogenic effects of IGF-1 and insulin on MCF-7 breast cancer cells.
Solomon
Curtis Scott
CS
Research Service, Denver VA Medical Center, Denver, Colorado 80220, USA.
Goalstone
Marc Lee
ML
D019883:Alkyl and Aryl Transferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002455:Cell Division; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007329:Insulin Antagonists / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors*; D009154:Mutation; D010766:Phosphorylation; D017368:Protein Prenylation; D021122:Protein Subunits; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D004273:DNA, Neoplasm; D007328:Insulin; D007329:Insulin Antagonists; D021122:Protein Subunits; D007334:Insulin-Like Growth Factor I; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D020742:rhoA GTP-Binding Protein