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STAT1 signaling is associated with acquired crossresistance to doxorubicin and radiation in myeloma cell lines
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Rolf Larsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. (Rolf Larsson)
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2007 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 120, no 1, 189-195 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2007. Vol. 120, no 1, 189-195 p.
Keyword [en]
Drug resistance, Microarray, Radiation resistance, STAT1
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-10560DOI: 10.1002/ijc.22291ISI: 000242653300027PubMedID: 17072862OAI: oai:DiVA.org:uu-10560DiVA: diva2:38328
Available from: 2008-06-29 Created: 2008-06-29 Last updated: 2017-12-11
In thesis
1. Molecular Screening for Target Discovery in Cancer
Open this publication in new window or tab >>Molecular Screening for Target Discovery in Cancer
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer is one of the major causes of death in the western world. Resistance to anti-cancer drugs and diagnostic difficulties are major obstacles to successful treatment. This thesis describes studies based on microarray expression analysis and high-throughput compound screening for identification of resistance mechanisms, drug targets and diagnostic markers.

In paper I-IV, we applied global expression analysis and measurements of drug response in a human tumor cell line panel to identify drug targets and resistance mechanisms. In paper I, we identified gene transcript levels that correlate with drug resistance and sensitivity. Both well known and new potential markers and mechanisms were identified. In paper II, we showed that STAT1 activity is associated with cross-resistance to both doxorubicin and radiation in vitro and that fludarabine can counteract STAT1 activity and reduce resistance. In Paper III-IV, cell lines were exposed to a compound library consisting of more than thousand different substances in a high-throughput screening effort. These studies revealed that cell line models of squamous cell carcinoma (Paper III) and drug resistant myeloma (Paper IV) are sensitive to phosphodiesterase inhibitors and glucocorticoids respectively. The target molecules for these drugs were over-expressed at the mRNA level and constitute likely explanations for the observed drug potency. In paper V, we identified mRNA markers for the distinction between two types of thyroid tumors, thyroid follicular adenomas and thyroid follicular carcinomas, by means of microarray expression analysis. Our results indicated that distinction between the two tumor types is possible with a small number of markers.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 42 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 162
Keyword
Genetics, Cancer, Drug resistance, Microarray, High-throughput screening, Genetik
Identifiers
urn:nbn:se:uu:diva-7086 (URN)91-554-6620-6 (ISBN)
Public defence
2006-09-21, Rudbecksalen, C11, Rudbecklaboratoriet, Uppsala, 13:15 (English)
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Available from: 2006-09-01 Created: 2006-09-01 Last updated: 2009-05-12Bibliographically approved

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Fryknäs, MårtenÖberg, FredrikRickardson, LindaRydåker, MariaGöransson, HannaGustafsson, MatsPettersson, UlfNygren, PeterLarsson, RolfIsaksson, Anders

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Fryknäs, MårtenÖberg, FredrikRickardson, LindaRydåker, MariaGöransson, HannaGustafsson, MatsPettersson, UlfNygren, PeterLarsson, RolfIsaksson, Anders
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Department of Genetics and PathologyClinical PharmacologyDepartment of Oncology, Radiology and Clinical ImmunologyDepartment of Medical Sciences
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International Journal of Cancer
Medical and Health Sciences

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