EGF-induced translocation of the adaptor protein She is involved in up-regulation of the tyrosine kinase c-Src in A431 cells

Abstract

According to Fearon and Vogelstein, the process of malignant transformation in intestinal cells is caused by stepwise gene mutations with phenotypic adenoma-carcinoma-sequence. COX inhibitors show tumorsuppressive effects both in vitro and in vivo. Since intestinal tumors of humans, rats and mice show overexpression of the COX-2 isoenzyme, the specific inhibition of COX-2 is considered to be a basic mechanism of tumor prevention. Protein kinase C (PKC) family plays an important role in signal transduction. PKCS isoenzyme is reported to be involved in cell differentiation and apoptosis onset. To investigate changes in PKCS expression and distribution under APC gene defect and COX-2 inhibition, we used the MIN-mouse model. Mice were treated with three different COX-inhibitors of various specificity over 60 days against control. Piroxicam, Sulindac, and Meloxicam were administered with drinking water in adequate doses. Formalin-fixed samples of the small intestine were investigated by indirect immunohistochemistry with antibodies against PKCS. Both in untreated and in Balb C mice, rare positive signals of PKCS were found mainly at the luminal surface of the villi. The cellular distribution was ubiquitous in the cytoplasm. In contrast, a distinct nuclear immunoreactivity was found under COX inhibition. PKCS immunoreactivity seemed to increase with COX-2 inhibitor specificity. These results corresponded with increased apoptotic activity (TUNEL, KLENOW) in the intestinal tissue after treatment with COX inhibitors. Considering that the translocation of PKCG from the cytosol to membrane structures and nucleus is a sign of its activation, a role for this isoenzyme in the regulation of the anticarcinogenic effects of COX-2 inhibition is to be concluded.