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https://hdl.handle.net/2440/61263
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Type: | Journal article |
Title: | Silencing of the insulin receptor isoform A favors formation of type 1 insulin-like growth factor receptor (IGF-IR) homodimers and enhances ligand-induced IGF-IR activation and viability of human colon carcinoma cells |
Author: | Brierley, G. Macaulay, S. Forbes, B. Wallace, J. Cosgrove, L. Macaulay, V. |
Citation: | Endocrinology, 2010; 151(4):1418-1427 |
Publisher: | Endocrine Soc |
Issue Date: | 2010 |
ISSN: | 0013-7227 0013-7227 |
Statement of Responsibility: | G.V. Brierley, S.L. Macaulay, B.E. Forbes, J.C. Wallace, L.J. Cosgrove and V.M. Macaulay |
Abstract: | Insulin receptor (IR) overexpression is common in cancers, with expression of the A isoform (IR-A, exon 11–) predominating over the B isoform. The IR-A signals a proliferative, antiapoptotic response to IGF-II, which itself can be secreted by tumors to establish an autocrine proliferative loop. Therefore, IGF-II signaling via the IR-A could mediate resistance to type 1 IGF receptor (IGF-IR) inhibitory drugs that are currently in development. This study addressed the role of the IR-A, using a small interfering RNA-based approach in SW480 human colon adenocarcinoma cells that coexpress the IGF-IR. Clonogenic survival was inhibited by depletion of the IGF-IR but not the IR-A, and dual receptor depletion had no greater effect than IGF-IR knockdown alone, suggesting that the IR-A could not compensate for IGF-IR loss. IGF-IR knockdown also resulted in a decrease in viability, whereas IR-A depletion resulted in increased viability. Consistent with this, upon IR-A depletion, we found a concomitant enhancement of IGF-IR activation by IGF-I and IGF-II, reduced formation of IGF-IR:IR-A hybrid receptors and increased IGF-IR homodimer formation. Together, these results suggest that IGF bioactivity is mediated more effectively by the IGF-IR than by the IR-A or receptor hybrids and that signaling via the IGF-IR is dominant to the IR-A in colon cancer cells that express both receptors. |
Keywords: | Cells, Cultured Cell Line Humans Indans Insulin Receptor, IGF Type 1 Receptor, Insulin Insulin-Like Growth Factor I Insulin-Like Growth Factor II Protein Isoforms RNA, Small Interfering Blotting, Western Flow Cytometry Transfection Reverse Transcriptase Polymerase Chain Reaction Immunoprecipitation Cell Survival Gene Silencing Dose-Response Relationship, Drug Protein Multimerization |
Rights: | Copyright © 2010 by The Endocrine Society |
DOI: | 10.1210/en.2009-1006 |
Published version: | http://dx.doi.org/10.1210/en.2009-1006 |
Appears in Collections: | Aurora harvest 5 Molecular and Biomedical Science publications |
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