p185c-erbB-2 signal enhances cisplatin-induced cytotoxicity in human breast carcinoma cells: association between an oncogenic receptor tyrosine kinase and drug-induced DNA repair.
Cancer Res
; 54(14): 3758-65, 1994 Jul 15.
Article
em En
| MEDLINE
| ID: mdl-7913407
ABSTRACT
The c-erbB-2 (HER-2/neu) protooncogene encodes an M(r) 185,000 transmembrane glycoprotein with intrinsic tyrosine kinase activity. Agonistic antibodies against p185c-erbB-2 enhance the cytotoxic effect of the DNA alkylator, cisplatin, against c-erbB-2-overexpressing human carcinoma cells (Hancock et al., Cancer Res., 514575-4580, 1991). We have studied the possible association between receptor signal transduction and cisplatin-mediated cytotoxicity utilizing the SKBR-3 human breast cancer cell line and the anti-p185 TAb 250 IgG1. TAb 250 induced tyrosine phosphorylation of p185 and the receptor substrate phospholipase C-gamma 1, as well as rapid association of these molecules in vivo. Simultaneously with phosphorylation, phospholipase C-gamma 1 catalytic activity measured in a [3H]phosphatidylinositol-4,5-bisphosphate hydrolysis assay was increased 61 +/- 12% above control. Preincubation of SKBR-3 cells with the tyrosine kinase inhibitor tyrphostin 50864-2 abrogated the enhancement of drug-mediated cell kill induced by TAb 250. The supraadditive drug/antibody effect was not seen in SKBR-3 cells with TAb 263, an anti-p185 IgG1 that does not induce receptor signaling or with TAb 250 in MDA-468 breast cancer cells which do not overexpress c-erbB-2. In addition, transforming growth factor-alpha increased cisplatin-induced cytotoxicity against NIH 3T3 cells overexpressing an epidermal growth factor receptor/c-erbB-2 chimera. Cellular uptake or efflux of [195mPt]cisplatin by SKBR-3 cells was not altered by TAb 250. Finally, simultaneous treatment of SKBR-3 cells with TAb 250 and cisplatin increased cisplatin/DNA intrastrand adduct formation and delayed the rate of adduct decay. Taken together these data support a direct association between p185c-erbB-2 signal transduction and inhibition of cisplatin-induced DNA repair.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
/
Transdução de Sinais
/
Proteínas Proto-Oncogênicas
/
Cisplatino
/
Receptores Proteína Tirosina Quinases
/
Reparo do DNA
/
Receptores ErbB
Tipo de estudo:
Risk_factors_studies
Limite:
Female
/
Humans
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
1994
Tipo de documento:
Article