STAT1 signaling is associated with acquired crossresistance to doxorubicin and radiation in myeloma cell lines.
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.
Fryknäs
Mårten
M
Department of Genetics and Pathology, Uppsala University, Sweden.
Dhar
Sumeer
S
Oberg
Fredrik
F
Rickardson
Linda
L
Rydåker
Maria
M
Göransson
Hanna
H
Gustafsson
Mats
M
Pettersson
Ulf
U
Nygren
Peter
P
Larsson
Rolf
R
Isaksson
Anders
A
D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D003429:Cross Reactions; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D004307:Dose-Response Relationship, Radiation; D004317:Doxorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005720:Gamma Rays; D020869:Gene Expression Profiling; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011836:Radiation Tolerance; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D004317:Doxorubicin; D004248:DNA (Cytosine-5-)-Methyltransferases; D014740:Vidarabine; C024352:fludarabine