Abstract
We have examined the role of erbB-2 expression in the modulation of cellular toxicity to cisplatin. We have demonstrated that treatment of NIH3T3-erbB-2 cells, which overexpress the p185erbB-2 product of the human erbB-2 gene, with a monoclonal antibody directed against the extracellular domain (TAb-250), results in enhanced cisplatin cytotoxicity. A similar enhancement was obtained when cells were exposed to herbimycin A and its analogue CP127 374, both of which inhibit tyrosine kinase activity. Using the host cell reactivation (HCR) of reporter gene expression from cisplatin-damaged plasmid and unscheduled DNA synthesis (UDS) following cisplatin treatment of cells, we have found that modulation of erbB-2 by TAb-250 was associated with inhibition of DNA repair. TAb-250 alone, under conditions which modulate DNA repair, slightly reduces the S-phase of the cell cycle, while cisplatin induced arrest at S and G2 phases. Combination of TAb-250 and cisplatin only slightly prevented cisplatin-induced S and G2 blocks. Since the ras pathway is one of the major signaling components coupled to erbB-2, we have examined the role of ras in DNA repair regulation. Transient expression of a ras dominant negative mutant, Asn-17-rasH, prevents DNA repair modulation by TAb-250, suggesting that the erbB-2 receptor regulates DNA repair mechanism(s), at least in part, through ras-coupled pathway(s).
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Yen, L., Zeng-Rong, N., You, XL. et al. Regulation of cellular response to cisplatin-induced DNA damage and DNA repair in cells overexpressing p185erbB-2 is dependent on the ras signaling pathway. Oncogene 14, 1827–1835 (1997). https://doi.org/10.1038/sj.onc.1201019
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DOI: https://doi.org/10.1038/sj.onc.1201019
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