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J. Biol. Chem., Vol. 276, Issue 30, 28562-28569, July 27, 2001
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From the Genotoxic stress leads to nuclear
translocation of the Y-box transcription factor YB-1 and enhanced
expression of the multidrug resistance gene MDR1. Because
hyperthermia is used for the treatment of colon cancer in combination
with chemoradiotherapy, we investigated the influence of hyperthermia
on YB-1 activity and the expression of multidrug resistance-related
genes. Here we report that hyperthermia causes YB-1 translocation from
the cytoplasm into the nucleus of human colon carcinoma cells HCT15 and
HCT116. Nuclear translocation of YB-1 was associated with increased
MDR1 and MRP1 gene activity, which is reflected
in strong efflux pump activity. However, a combination of hyperthermia
and drug treatment effectively reduced cell survival of the HCT15 and
HCT116 cells. These results demonstrate that activation of
MDR1 and MRP1 gene expression and increased efflux pump activity after hyperthermia were insufficient to cause an
increase in drug resistance in colon cancer cell lines. The ability of hyperthermia to abrogate drug resistance in the presence of
an increase in functional MDR proteins may provide an explanation for
the efficacious results seen in the clinic in colon cancer patients
treated with a combination of hyperthermia and chemotherapy.
Hyperthermia-induced Nuclear Translocation of
Transcription Factor YB-1 Leads to Enhanced Expression of Multidrug
Resistance-related ABC Transporters*
§,,,,
Max-Delbrück Center for Molecular
Medicine, Robert-Rössle Strasse 10, 13092 Berlin, Germany;
¶ Charité, Humboldt-University, Campus Berlin-Buch,
Robert-Rössle Clinic, Lindenberger Weg 80, 13122 Berlin, Germany;
and the Institute for Transplantation Diagnostics and Cell
Therapy, Heinrich-Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
*
This work was supported by Grant SFB 273 from the Deutsche
Forschungsgemeinschaft (to U. S.) and by a grant from the Berliner Krebshilfe (to H.-D. R.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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