Oncogenic H-Ras up-regulates expression of ERCC1 to protect cells from platinum-based anticancer agents.
Tumors frequently contain mutations in the ras genes, resulting in the constitutive activation of the Ras-activated signaling pathway. The activation of Ras is involved not only in tumor progression but also in the development of resistance of the tumor cells to platinum-based chemotherapeutic agents. To investigate the potential mechanisms underlying this resistance, we analyzed the effect of activated H-Ras on the expression of the nucleotide excision repair genes. Here we identified ERCC1, which is one of the key enzymes involved in nucleotide excision repair, as being markedly up-regulated by the activated H-Ras. From promoter analysis of ERCC1, an increase in the Ap1 transcriptional activity as a result of the expression of the oncogenic H-Ras was found to be crucial for this induction. In addition, ERCC1 small interfering RNA expression was shown to reduce the oncogenic H-Ras-mediated increase in the DNA repair activity as well as to suppress the oncogenic H-Ras-mediated resistance of the cells to platinum-containing chemotherapeutic agents. These results suggest that the oncogenic H-Ras-induced ERCC1, which activates the DNA repair capacity, may be involved in the protection of the cells against platinum-based anticancer agents.
Youn
Cha-Kyung
CK
Research Center for Proteineous Materials, School of Medicine, Chosun University, Gwangju, Korea.
Kim
Mi-Hwa
MH
Cho
Hyun-Ju
HJ
Kim
Hong-Beum
HB
Chang
In-Youb
IY
Chung
Myung-Hee
MH
You
Ho Jin
HJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016190:Carboplatin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004260:DNA Repair / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004720:Endonucleases / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D015689:Oncogene Protein p21(ras) / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000096:biosynthesis / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D000077150:Oxaliplatin; D016190:Carboplatin; C071447:ERCC1 protein, human; D004720:Endonucleases; C499360:Ercc1 protein, mouse; D015689:Oncogene Protein p21(ras); D002945:Cisplatin