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BMC Cancer. 2012; 12: 318.
Published online Jul 28, 2012. doi:  10.1186/1471-2407-12-318
PMCID: PMC3488543
Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma
Lina Y Dimberg,1 Anna Dimberg,1 Karolina Ivarsson,1 Mårten Fryknäs,1,2 Linda Rickardson,2 Gerard Tobin,1 Simon Ekman,1 Rolf Larsson,2 Urban Gullberg,3 Kenneth Nilsson,1 Fredrik Öberg,1 and Helena Jernberg Wiklundcorresponding author1
1Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, S- 751 85, Sweden
2Department of Medical Sciences, Uppsala University, Uppsala, Sweden
3Department of Laboratory Medicine, Lund University, Lund, Sweden
corresponding authorCorresponding author.
Lina Y Dimberg: linadimberg/at/yahoo.se; Anna Dimberg: Anna.dimberg/at/igp.uu.se; Karolina Ivarsson: karolinai/at/hotmail.com; Mårten Fryknäs: Marten.Fryknas/at/medsci.uu.se; Linda Rickardson: Linda.Rickardson/at/medsci.uu.se; Gerard Tobin: gerard_tobin/at/hotmail.com; Simon Ekman: simon.ekman/at/akademiska.se; Rolf Larsson: Rolf.Larsson/at/medsci.uu.se; Urban Gullberg: urban.gullberg/at/hematologi.lu.se; Kenneth Nilsson: Kenneth.Nilsson/at/igp.uu.se; Fredrik Öberg: fredrik.oberg/at/igp.uu.se; Helena Jernberg Wiklund: helena.jernberg_wiklund/at/igp.uu.se
Received March 12, 2012; Accepted July 12, 2012.
Abstract
Background
Multiple myeloma (MM) is at present an incurable malignancy, characterized by apoptosis-resistant tumor cells. Interferon (IFN) treatment sensitizes MM cells to Fas-induced apoptosis and is associated with an increased activation of Signal transducer and activator of transcription (Stat)1. The role of Stat1 in MM has not been elucidated, but Stat1 has in several studies been ascribed a pro-apoptotic role. Conversely, IL-6 induction of Stat3 is known to confer resistance to apoptosis in MM.
Methods
To delineate the role of Stat1 in IFN mediated sensitization to apoptosis, sub-lines of the U-266-1970 MM cell line with a stable expression of the active mutant Stat1C were utilized. The influence of Stat1C constitutive transcriptional activation on endogenous Stat3 expression and activation, and the expression of apoptosis-related genes were analyzed. To determine whether Stat1 alone would be an important determinant in sensitizing MM cells to apoptosis, the U-266-1970-Stat1C cell line and control cells were exposed to high throughput compound screening (HTS).
Results
To explore the role of Stat1 in IFN mediated apoptosis sensitization of MM, we established sublines of the MM cell line U-266-1970 constitutively expressing the active mutant Stat1C. We found that constitutive nuclear localization and transcriptional activity of Stat1 was associated with an attenuation of IL-6-induced Stat3 activation and up-regulation of mRNA for the pro-apoptotic Bcl-2 protein family genes Harakiri, the short form of Mcl-1 and Noxa. However, Stat1 activation alone was not sufficient to sensitize cells to Fas-induced apoptosis. In a screening of > 3000 compounds including bortezomib, dexamethasone, etoposide, suberoylanilide hydroxamic acid (SAHA), geldanamycin (17-AAG), doxorubicin and thalidomide, we found that the drug response and IC50 in cells constitutively expressing active Stat1 was mainly unaltered.
Conclusion
We conclude that Stat1 alters IL-6 induced Stat3 activity and the expression of pro-apoptotic genes. However, this shift alone is not sufficient to alter apoptosis sensitivity in MM cells, suggesting that Stat1 independent pathways are operative in IFN mediated apoptosis sensitization.
Keywords: Hematopoetic malignancies, Multiple myeloma, Apoptosis, IFN, Stat1, Stat3, Drug sensitivity
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