Selective Disruption of Insulin-like Growth Factor-1 (IGF-1) Signaling via Phosphoinositide-dependent Kinase-1 Prevents the Protective Effect of IGF-1 on Human Cancer Cell Death
Copyright policy )Selective Disruption of Insulin-like Growth Factor-1 (IGF-1) Signaling via Phosphoinositide-dependent Kinase-1 Prevents the Protective Effect of IGF-1 on Human Cancer Cell Death
Insulin-like growth factor-1 (IGF-1) signaling system exerts a broad antiapoptotic function and plays a crucial role in resistance to anticancer therapies. Exposure of MCF-7 breast cancer cells to IGF-1 rapidly and transiently induced tyrosine phosphorylation and activation of phosphoinositide-dependent kinase-1 (PDK1). This was paralleled by Akt/protein kinase B and protein kinase C-zeta phosphorylation, at Thr(308) and Thr(410), respectively. IGF-1 treatment also enhanced PDK1 interaction with IGF-1 receptor (IGF-1R) in intact MCF-7 cells. Pulldown assays revealed that PDK1 bound IGF-1R in vitro and that the region encompassing amino acids 51-359 of PDK1 was necessary for the interaction. Synthetic peptides corresponding to IGF-1R C terminus amino acids 1295-1337 (C43) and to PDK1 amino acids 114-141 reduced in vitro IGF-1R/PDK1 interaction in a concentration-dependent manner. Loading of fluoresceinated-C43 (fluorescein isothiocyanate (FITC)-C43) into MCF-7 cells significantly reduced IGF-1R/PDK1 interaction and phosphorylation of PDK1 substrates. Moreover, FITC-C43 intracellular loading reverted the protective effect of IGF-1 on growth factor deprivation-induced cell death. Finally, the inhibition of IGF-1R/PDK1 interaction and signaling by FITC-C43 was accompanied by 2-fold enhanced killing capacity of cetuximab in human GEO colon adenocarcinoma cells and was sufficient to restore cell death in cetuximab-resistant cell clones. Thus, disruption of PDK1 interaction with IGF-1R reduces IGF-1 survival effects in cancer cells and may enhance cell death by anticancer agents.
Cell Death, Cell Survival, IGF-1; PDK-1; IGF-1R/PDK-1 interaction, Antibodies, Monoclonal, Cetuximab, Protein Serine-Threonine Kinases, Antibodies, Monoclonal, Humanized, Peptide Fragments, Receptor, IGF Type 1, 3-Phosphoinositide-Dependent Protein Kinases, Mice, Drug Resistance, Neoplasm, Cell Line, Tumor, IGF-1, Animals, Humans, Insulin-Like Growth Factor I, Protein Binding, Signal Transduction
Cell Death, Cell Survival, IGF-1; PDK-1; IGF-1R/PDK-1 interaction, Antibodies, Monoclonal, Cetuximab, Protein Serine-Threonine Kinases, Antibodies, Monoclonal, Humanized, Peptide Fragments, Receptor, IGF Type 1, 3-Phosphoinositide-Dependent Protein Kinases, Mice, Drug Resistance, Neoplasm, Cell Line, Tumor, IGF-1, Animals, Humans, Insulin-Like Growth Factor I, Protein Binding, Signal Transduction
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