Hyperthermia-induced nuclear translocation of transcription factor YB-1 leads to enhanced expression of multidrug resistance-related ABC transporters.
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.
Stein
U
U
Max-Delbrück Center for Molecular Medicine, Robert-Rössle Strasse 10, 13092 Berlin, Germany. ustein@mdc-berlin.de
Jürchott
K
K
Walther
W
W
Bergmann
S
S
Schlag
P M
PM
Royer
H D
HD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000494:pharmacology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins; D004317:Doxorubicin / Q000494:pharmacology; D005334:Fever; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D017930:Genes, Reporter; D006801:Humans; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D010957:Plasmids / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012235:Rhodamines / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D051840:Y-Box-Binding Protein 1
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D022762:CCAAT-Enhancer-Binding Proteins; D015500:Chloramphenicol O-Acetyltransferase; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D012313:RNA; D012235:Rhodamines; D014157:Transcription Factors; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human