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Targeting the Insulin-like Growth Factor Receptor (IGF-IR) Survival Pathways in Multiple Myeloma Using Selective IGF-IR Tyrosine Kinase Inhibitors
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
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Article in journal (Refereed) Submitted
URN: urn:nbn:se:uu:diva-90842OAI: oai:DiVA.org:uu-90842DiVA: diva2:163337
Available from: 2003-09-05 Created: 2003-09-05Bibliographically approved
In thesis
1. The Regulation of Growth and Survival in Human Multiple Myeloma Cells by IGF-I Receptor Signaling
Open this publication in new window or tab >>The Regulation of Growth and Survival in Human Multiple Myeloma Cells by IGF-I Receptor Signaling
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Multiple myeloma (MM) is an incurable B-cell malignancy mainly localized to the bone marrow. Our aim was to examine the growth- and survival-promoting role of the IGF-IR and its downstream signaling components in MM cells to identify potential targets for therapy.

Octreotide, a somatostatin analog that has been demonstrated to interfere with the actions of IGF-I, induced growth inhibition in both IL-6-dependent and IL-6-independent MM cell lines expressing the somatostatin receptors sst2, sst3 and sst5. Additionally, a slight pro-apoptotic effect could be observed in a few cell lines. In primary MM cells octreotide induced apoptosis, an effect that was abrogated by exogenously added IGF-I, but not by IL-6.

Inhibition of IGF-I signaling in Karpas 707 cells, using either the anti-IGF-IR antibody αIR3 or the PI 3-K inhibitors LY294002 and wortmannin, increased sensitivity to apoptosis induced by dexamethasone. Exogenously added IGF-I prevented dexamethasone-induced apoptosis, an effect that could partly be mimicked by the pharmacological GSK-3β inhibitors LiCl and SB415286. Thus, we suggest the GSK-3β as an important mediator of the anti-apoptotic effects of IGF-IR signaling in MM.

Using rapamycin we selectively inhibited mTOR, a phosphoprotein downstream of the IGF-IR. In MM cell lines rapamycin induced G0/G1-arrest, an effect being associated with an increase of the cyclin-dependent kinase inhibitor p27 and a decrease of the cyclins D2, D3 and E. Interestingly, in primary MM cells rapamycin induced apoptosis. Moreover, rapamycin potentiated dexamethasone-induced apoptosis, an effect that was associated with a downregulation of the anti-apoptotic protein survivin. Strikingly, the combinatorial treatment with rapamycin and dexamethasone suppressed the anti-apoptotic effects of exogenously added IGF-I and IL-6, thus suggesting this drug-combination to be active also in vivo.

Two newly developed, selective IGF-I RTK inhibitors proved to be very effective in MM cell lines and in primary MM cells providing 50-90% growth inhibition within 48 h of incubation. The inhibitors induced massive apoptosis together with a prominent cell cycle arrest in the G2/M-phase. Importantly, the IGF-I RTK inhibitors downregulated the tyrosine phosphorylation of the IGF-IR β-chain but not of the insulin receptor β-chain.

In conclusion, the IGF-IR potently promotes growth and survival of MM cells. Therefore, interfering with the IGF-IR signaling pathway might be a suitable strategy to improve MM treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 69 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1289
Pathology, Multiple myeloma, IGF-IR, apoptosis, somatostatin, octreotide, dexamethasone, GSK-3, mTOR, rapamycin, RTK inhibitor, Patologi
National Category
Cell and Molecular Biology
urn:nbn:se:uu:diva-3586 (URN)91-554-5740-1 (ISBN)
Public defence
2003-09-27, Rudbecksalen, Rudbecklaboratoriet, C11, Uppsala, 13:15
Available from: 2003-09-05 Created: 2003-09-05Bibliographically approved

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