Association between the level of ERCC-1 expression and the repair of cisplatin-induced DNA damage in human ovarian cancer cells.
Nucleotide excision repair (NER) is responsible for the repair of platinum-DNA lesions. ERCC-1 is a critical gene within the NER pathway, and cells without a functional ERCC-1 do not repair cisplatin-caused DNA damage. The present study was therefore designed to evaluate the relationship between the expression of ERCC-1 and the repair of cisplatin-induced DNA adducts in human ovarian cancer cells in vitro. One hour exposure of MCAS cells to cisplatin yielded an approximately two-fold increment in the levels of ERCC-1 mRNA and ERCC-1 protein, as determined, respectively, by Northern and Western blottings. In addition, nuclear run-on assay showed that ERCC-1 gene transcription rate was increased to about the same extent as steady-state ERCC-1 mRNA and protein, in response to cisplatin treatment. However, the levels of ERCC-1 mRNA, ERCC-1 protein, and ERCC-1 transcript in MCAS cells are two-fold lower than those in A2780/CP70 cells, as previously reported. Furthermore, the repair of cisplatin-DNA adducts in MCAS cells, as measured by atomic absorption spectrometry, is also nearly two-fold less than that in A2780/CP70 cells, indicating a strong association between the level of ERCC-1 expression and the activity of excision repair in these two human ovarian tumor cell lines. These results suggest that ERCC-1 may be a useful marker to monitor the repair of platinum-DNA damage in tumor cells, and further highlight that potential pharmacological approaches which specifically inhibit ERCC-1 expression may increase cellular sensitivity to cisplatin.
Li
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Developmental Therapeutics Department, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Yu
J J
JJ
Mu
C
C
Yunmbam
M K
MK
Slavsky
D
D
Cross
C L
CL
Bostick-Bruton
F
F
Reed
E
E
D002467:Cell Nucleus / Q000378:metabolism; D002945:Cisplatin / Q000032:analysis* / Q000633:toxicity*; D018736:DNA Adducts / Q000032:analysis*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D010051:Ovarian Neoplasms; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D018736:DNA Adducts; D004268:DNA-Binding Proteins; D011506:Proteins; D012333:RNA, Messenger; C057270:cisplatin-DNA adduct; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin