Loss of insulin-like growth factor II receptor expression promotes growth in cancer by increasing intracellular signaling from both IGF-I and insulin receptors.
The insulin-like growth factor-II receptor (IGF-IIR) is frequently mutated or deleted in some malignant human tumors, suggesting that the IGF-IIR is a tumor suppressor. However, the exact mechanism by which IGF-IIR suppresses growth in tumors has not been definitively established. We demonstrate that IGF-IIR-deficient murine L cells (D9) have higher growth rates than IGF-IIR-positive L cells (Cc2) in response to IGF-II. IGF-II levels are higher in growth-conditioned medium from D9 versus Cc2 cells. Receptor neutralization studies and measurements of insulin receptor substrate 1 phosphorylation confirm that the enhanced growth of D9 cells is due to increased stimulation of the IGF-I and insulin receptors by IGF-II. In contrast, the levels of secreted latent and active transforming growth factor beta (TGF-beta) are similar for both D9 and Cc2 cells, indicating that the slower growth of Cc2 cells is not due to activation of latent TGF-beta by IGF-IIR and growth inhibition. The results directly demonstrate that down regulation of the IGF-IIR promotes the growth of transformed D9 cells by sustaining IGF-II, which binds to and activates IGF-IR and insulin receptor to increase intracellular growth signals.
Division of Molecular and Cellular Biochemistry, Loyola University Medical Center, Maywood, Illinois 60153, USA.
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Osipo
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Dorman
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Frankfater
D000818:Animals; D002417:Cattle; D002455:Cell Division; D017077:Culture Media, Conditioned; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000494:pharmacology; D007424:Intracellular Fluid; D007739:L Cells; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D017077:Culture Media, Conditioned; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D017527:Receptor, IGF Type 2; D016212:Transforming Growth Factor beta; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin