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
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(754 views) Alberobello AT, D'Esposito V, Marasco D, Doti N, Ruvo M, Bianco R, Tortora G, Esposito I, Fiory F, Miele C, Beguinot F, Formisano P
Keywords: Adenocarcinoma Cells, Anti-Cancer Agents, Anti-Cancer Therapies, Antiapoptotic, C Terminus, Cancer Cells, Cetuximab, Concentration-Dependent, Fluorescein Isothiocyanate, Growth Factor, Human Cancer Cells, In-Vitro, Insulin-Like Growth Factor-1, Mcf-7 Breast Cancer Cells, Mcf-7 Cells, Phosphoinositides, Protective Effects, Protein Kinase C, Pulldown Assays, Resistant Cells, Signaling Systems, Synthetic Peptide, Tyrosine Phosphorylation, Amino Acids, Bioactivity, Cell Death, Organic Acids, Phosphatases, Clone Cells, Phosphoinositide Dependent Protein Kinase 1, Protein Kinase C Zeta, Somatomedin C, Somatomedin C Receptor, 3 Phosphoinositide Dependent Protein Kinase, 3-Phosphoinositide-Dependent Protein Kinase, Monoclonal Antibody, Peptide Fragment, Protein Serine Threonine Kinase, Amino Acid Sequence, Animal Cell, Apoptosis, Article, Cancer Inhibition, Carboxy Terminal Sequence, Cell Clone, Cell Strain Mcf 7, Colon Adenocarcinoma, Controlled Study, Enzyme Activation, Enzyme Substrate, Human Cell, Hydrophobicity, In Vitro Study, Nonhuman, Priority Journal, Protein Phosphorylation, Protein Protein Interaction, Signal Transduction, Cell Survival, Drug Resistance, Metabolism, Mouse, Physiology, Protein Binding, Synthesis, Tumor Cell Line, Antibodies, Neoplasm, Protein-Serine-Threonine Kinases, Igf Type 1,
Affiliations: *** IBB - CNR ***
Dipartimento di Biologia e Patologia Cellulare e Molecolare, Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale Delle Ricerche (CNR), Università di Napoli Federico II, 80131 Naples, Italy
Dipartimento Delle Scienze Biologiche, Università di Napoli Federico II, 80131 Naples, Italy
Istituto di Biostutture e Bioimmagini del CNR, Università di Napoli Federico II, 80131 Naples, Italy
Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università di Napoli Federico II, 80131 Naples, Italy
References: Not available.
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.
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
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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