1. Activation of the insulin-like growth factor 1 signaling pathway by the antiapoptotic agents aurintricarboxylic acid and evans blue.
- Author
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Beery R, Haimsohn M, Wertheim N, Hemi R, Nir U, Karasik A, Kanety H, and Geier A
- Subjects
- 3T3 Cells, Animals, Aurintricarboxylic Acid metabolism, Cell Division physiology, Cell Survival physiology, Enzyme Activation, Evans Blue metabolism, Humans, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Mice, Mitogen-Activated Protein Kinases metabolism, Phosphatidylinositol 3-Kinases metabolism, Phosphoproteins metabolism, Phosphorylation, Proto-Oncogene Proteins physiology, Proto-Oncogene Proteins c-akt, Receptor, IGF Type 1 metabolism, Recombinant Proteins, Tumor Cells, Cultured pathology, Tumor Cells, Cultured physiology, Tyrosine metabolism, Apoptosis drug effects, Aurintricarboxylic Acid pharmacology, Evans Blue pharmacology, Insulin-Like Growth Factor I physiology, Protein Serine-Threonine Kinases, Signal Transduction drug effects
- Abstract
Aurintricarboxylic acid (ATA), an endonuclease inhibitor, prevents the death of a variety of cell types in culture. Previously we have shown that ATA, similar to insulin-like growth factor I (IGF-I), protected MCF-7 cells against apoptotic death induced by the protein synthesis inhibitor cycloheximide. Here we show that ATA and a polysulfonated aromatic compound, Evans blue (EB), similar to IGF-I, promote survival and increase proliferation of MCF-7 cells in serum-free culture medium. This may suggest a common signaling pathway shared by the aromatic polyanions and IGF-I. Therefore, the ability of these aromatic compounds to activate the signal transduction pathway of IGF-I was examined. We found that ATA and EB mimicked the IGF-I effect on tyrosine phosphorylation of the IGF-I receptor (IGF-IR) and its major substrates, insulin receptor substrate-1 (IRS-1) and IRS-2; induced the association of these substrates with phosphatidylinositol 3-kinase and Grb2; and activated Akt kinase and p42/p44 mitogen-activated protein kinases. ATA and EB competed for IGF-I binding to the IGF-IR. ATA was found to be selective for the IGF-IR, whereas EB also activated the insulin receptor. Upon fractionation of commercial ATA by size exclusion chromatography, we found that fractions that enhanced the intensity of tyrosyl-phosphorylated IRS-1/IRS-2 also increased the survival of MCF-7 cells in the presence of cycloheximide, whereas fractions devoid of IRS phosphorylation activity had no survival ability. Taken together, these results suggest that the survival/proliferation-promoting effects of ATA and EB in MCF-7 cells are transduced via the IGF-IR signaling pathway.
- Published
- 2001
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