Increase of the resistance of human cervical carcinoma cells to cisplatin by inhibition of the MEK to ERK signaling pathway partly via enhancement of anticancer drug-induced NF kappa B activation.
In this study, we showed that suppression of the MEK-ERK transduction pathway by a selective inhibitor, 2'-amino-3'-methoxyflavone (PD98059), increased drug resistance of SiHa cells to cisplatin, but not to another common anticancer drug, doxorubicin. The downstream mechanism of this discrepant cellular response was investigated. Both cisplatin and doxorubicin activated nuclear ERK2 and nuclear transcription factor kappa B (NF kappa B) of SiHa cells. However, suppression of the MEK-ERK2 pathway by PD98059 resulted in a further enhancement of cisplatin-induced NF kappa B activation, while no further regulation of NF kappa B was noted in doxorubicin-treated cells. The activation of NF kappa B by cisplatin or doxorubicin was not due to the degradation of cytoplasmic I kappa B alpha, as demonstrated by western blotting. Transfection of a dominant negative I kappa B alpha resulted in a markedly diminished PD98059-induced cisplatin resistance in SiHa cells. Our results suggest that the MEK-ERK signaling pathway plays a role in the chemosensitivity of SiHa cells, and suppression of this pathway increases cisplatin resistance partly via an increase of NF kappa B activation. The mechanism responsible for the discrepant effect of PD98059 on NF kappa B activation and hence the chemosensitivity of SiHa cells towards cisplatin and doxorubicin remains to be investigated.
Yeh
Pei Yen
PY
Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
Chuang
Shuang-En
SE
Yeh
Kun-Huei
KH
Song
Ying Chyi
YC
Ea
Chee-Kwee
CK
Cheng
Ann-Lii
AL
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms; D048051:p38 Mitogen-Activated Protein Kinases
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D005419:Flavonoids; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D004317:Doxorubicin; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002945:Cisplatin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one