Oncogenic H-Ras up-regulates expression of ERCC1 to protect cells from platinum-based anticancer agents

• Published in: Cancer research (Chicago, Ill.) Ill.), 2004-07, Vol.64 (14), p.4849-4857
• Main Authors: YOUN, Cha-Kyung, KIM, Mi-Hwa, CHO, Hyun-Ju, KIM, Hong-Beum, CHANG, In-Youb, CHUNG, Myung-Hee, HO JIN YOU
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Binding Sites; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Carboplatin - pharmacology; Cell Line, Tumor; Cisplatin - pharmacology; DNA Repair - physiology; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; Drug Resistance, Neoplasm; Endonucleases - biosynthesis; Endonucleases - genetics; Gene Expression Regulation, Neoplastic; Humans; Medical sciences; Mice; NIH 3T3 Cells; Oncogene Protein p21(ras) - biosynthesis; Oncogene Protein p21(ras) - genetics; Oncogene Protein p21(ras) - physiology; Organoplatinum Compounds - pharmacology; Pharmacology. Drug treatments; Promoter Regions, Genetic; RNA, Small Interfering - biosynthesis; RNA, Small Interfering - genetics; Transcription Factor AP-1 - physiology; Transcriptional Activation; Transfection; Tumors; Up-Regulation
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-0348

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.