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Ectopic and IFN-induced expression of Fas overcomes resistance to Fas-mediated apoptosis in multiple myeloma cells
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
Vise andre og tillknytning
2005 (engelsk)Inngår i: Blood, ISSN 1528-0020, Vol. 106, nr 4, s. 1346-1354Artikkel i tidsskrift (Fagfellevurdert) Published
sted, utgiver, år, opplag, sider
2005. Vol. 106, nr 4, s. 1346-1354
Identifikatorer
URN: urn:nbn:se:uu:diva-94752OAI: oai:DiVA.org:uu-94752DiVA, id: diva2:168720
Tilgjengelig fra: 2006-09-08 Laget: 2006-09-08 Sist oppdatert: 2009-12-04bibliografisk kontrollert
Inngår i avhandling
1. Apoptosis Regulation in Multiple Myeloma
Åpne denne publikasjonen i ny fane eller vindu >>Apoptosis Regulation in Multiple Myeloma
2006 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Multiple myeloma (MM) is a virtually incurable B cell malignancy of the bone marrow. One important part of tumor progression and an obstacle for successful therapy is resistance to apoptosis. To combat this resistance, the mechanisms of apoptosis and survival in MM must be better defined.

In this thesis, we identified Fas up-regulation as a mechanism underlying interferon (IFN)-mediated sensitization to Fas-induced apoptosis in the MM cell line U-266-1970. IFN treatment induced activation of signal transducer and activator of transcription (Stat)1 but, intriguingly, also attenuated activation of MM survival factor Stat3.

Exploring the role of Stat1 further, we established sub-lines of U-266-1970 with a stable over-expression of Stat1 and of its active mutant Stat1C. These sub-lines displayed a decreased expression and activation of Stat3, and an altered expression of apoptosis-related genes Harakiri, Bcl-2 and Mcl-1. In a drug library screening, Stat1 over-expression was associated with an increased sensitivity to Fas-induced apoptosis and, conversely, an increased resistance to several drugs, including the cyclin dependent kinase (cdk)1 inhibitor CGP74514A. We conclude that Stat1 over-expression does not confer a general resistance or sensitivity to apoptosis in MM, but may strongly affect the response to some specific drugs.

We also explored the effects of picropodophyllin (PPP), an inhibitor of the insulin-like growth factor I (IGF-I) receptor tyrosine kinase (RTK), in MM. PPP selectively inhibited the IGF-I RTK activity without inhibiting the insulin RTK activity. Furthermore, PPP potently induced cell cycle arrest and apoptosis in all MM cell lines and patient samples tested, also in the presence of survival factors IGF-I and IL-6. We conclude that PPP has great therapeutic potential in MM

Finally, we examined the expression and regulation of the inhibitors of apoptosis proteins (IAPs) in a panel of MM cell lines and patient samples. The glucocorticoid dexamethasone, which is used in MM therapy, induced a transient up-regulation and a subsequent down-regulation of c-IAP2, as well as a down-regulation of XIAP, possibly influencing the sensitivity to apoptosis induced by this drug. Supporting this notion, abrogation of IGF-IR signaling by PPP, which sensitizes MM cells to dexamethasone-induced apoptosis, enhanced the down-regulation of c-IAP2 and XIAP.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2006. s. 60
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 166
Emneord
Biomedicine, multiple myeloma, apoptosis, survival, IFN, Stat1, Stat3, IGF-I, RTK inhibitor, PPP, IAP, Fas/CD95, dexamethasone, Biomedicin
Identifikatorer
urn:nbn:se:uu:diva-7099 (URN)91-554-6629-X (ISBN)
Disputas
2006-09-29, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds Väg 20, Uppsala, 09:15
Opponent
Veileder
Tilgjengelig fra: 2006-09-08 Laget: 2006-09-08bibliografisk kontrollert

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