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STAT1 signaling is associated with acquired crossresistance to doxorubicin and radiation in myeloma cell lines

✍ Scribed by Mårten Fryknäs; Sumeer Dhar; Fredrik Öberg; Linda Rickardson; Maria Rydåker; Hanna Göransson; Mats Gustafsson; Ulf Pettersson; Peter Nygren; Rolf Larsson; Anders Isaksson

Book ID
102273735
Publisher
John Wiley and Sons
Year
2006
Tongue
French
Weight
309 KB
Volume
120
Category
Article
ISSN
0020-7136

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✦ Synopsis

Abstract

The myeloma cell line RPMI 8226/S and its doxorubicin resistant subline 8226/Dox40 were used as models to explore the potential importance of the STAT1 signaling pathway in drug and radiation resistance. The 40‐fold doxorubicin resistant subline 8226/Dox40 was found to be crossresistant to single doses of 4 and 8 Gy of radiation. A genome‐wide mRNA expression study comparing the 8226/Dox40 cell line to its parental line was performed to identify the underlying molecular mechanisms. Seventeen of the top 50 overexpressed genes have previously been implicated in the STAT1 signaling pathway. STAT1 was over expressed both at the mRNA and protein level. Moreover, analyses of nuclear extracts showed higher abundance of phosphorylated STAT1 (Tyr 701) in the resistant subline. Preexposure of the crossresistant cells to the STAT1 inhibiting drug fludarabine reduced expression of overexpressed genes and enhanced the effects of both doxorubicin and radiation. These results show that resistance to doxorubicin and radiation is associated with increased STAT1 signaling and can be modulated by fludarabine. The data support further development of therapies combining fludarabine and radiation. © 2006 Wiley‐Liss, Inc.

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