<p>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. </p><p>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.</p><p>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.</p><p>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. </p><p>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. </p><p>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.</p>
Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-3586 |
Date | January 2003 |
Creators | Strömberg, Thomas |
Publisher | Uppsala University, Department of Genetics and Pathology, Uppsala : Acta Universitatis Upsaliensis |
Source Sets | DiVA Archive at Upsalla University |
Language | English |
Detected Language | English |
Type | Doctoral thesis, comprehensive summary, text |
Relation | Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 0282-7476 ; 1289 |
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