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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
Statement of
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
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
Reverse Transcriptase Polymerase Chain Reaction
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:
Appears in Collections:Aurora harvest 5
Molecular and Biomedical Science publications

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