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Sensitization to dexamethasone-induced apoptosis by abrogation of insulin-like growth factor (IGF)-1 receptor signaling is associated with regulation of inhibitors of apoptosis proteins (IAP) in multiple myeloma cells.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
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Manuscript (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-96348OAI: oai:DiVA.org:uu-96348DiVA: diva2:170894
Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Mechanisms of Sensitization to Apoptosis in Multiple Myeloma
Open this publication in new window or tab >>Mechanisms of Sensitization to Apoptosis in Multiple Myeloma
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Multiple myeloma (MM) is a hematological tumor of plasma blast/plasma cell origin heterogeneous with respect to the morphological differentiation stage of the tumor cells, genetic alterations and course of disease. A challenge in MM research is to overcome resistance to therapy, which inevitably arises. In this thesis, we have used different strategies to sensitize MM cells to apoptosis and explored possible mechanisms of apoptotic control by the insulin-like growth factor-1 receptor (IGF-1R) survival pathway.

mTOR is a key molecule in the regulation of translation activated by survival signaling pathways in MM. We demonstrate that the mTOR-inhibitor rapamycin alone induced apoptosis in primary MM cells. In addition, rapamycin sensitized MM cells to apoptosis induced by dexamethasone, a glucocorticoid frequently used in MM therapy. MM survival factors IGF-1 and IL-6 could neither restore phosphorylation of the mTOR target p70S6K, nor cell growth inhibited by rapamycin and dexamethasone.

To study the regulation of inhibitors of apoptosis (IAP), we induced apoptosis and cell cycle arrest with dexamethasone and simultaneously abrogated IGF-1R signaling using the antagonistic antibody αIR3 or the selective IGF-1R inhibitor picropodophyllin (PPP). Dexamethasone transiently up-regulated c-IAP2. The subsequent down-regulation of c-IAP2 and XIAP was associated with the onset of apoptosis. c-IAP2 and XIAP levels further decreased when enhancing dexamethasone-induced apoptosis using αIR3 or PPP indicating a role for IAPs in regulating resistance to apoptosis in MM.

Finally, we explored glycogen synthase kinase (GSK)3 as a possible pro-apoptotic molecule and its role in regulating sensitization to apoptosis. We show that inhibition of GSK3 counteracts growth inhibition induced by dexamethasone alone and in combinatorial treatments with inhibitors against PI 3-kinase, mitogen-activated protein kinase (MEK), mTOR and IGF-1R. CT99021 also reversed cell cycle arrest induced by LY294002 or rapamycin. Importantly, the GSK3 inhibitor CT99021 sustained viability in untreated and dexamethasone-treated primary MM cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 49 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 283
Keyword
Pathology, multiple myeloma, apoptosis, IGF-1, mTOR, IAP, GSK3, rapamycin, PPP, dexamethasone, CT99021, Patologi
Identifiers
urn:nbn:se:uu:diva-8280 (URN)978-91-554-7002-9 (ISBN)
Public defence
2007-11-23, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15
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Available from: 2007-11-01 Created: 2007-11-01Bibliographically approved

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