MECHANISTIC STUDY OF THE ROLE OF TYROSINE KINASE SIGNAL TRANSDUCTION IN THE INVASION POTENTIAL AND APOPTOSIS OF TUMOR CELLS

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Activation of Src and Ras has been demonstrated be closely associated with the pathogenesis and metastatic potential of many human tumors. However, the role of these oncogenes in the drug sensitivity and invasion process remain to be clarified. We examined the role of Src and Ras on these processes, using HAG-1 human epithelial cell lines transfected with v-src and activated H-ras. First we examined the potential role of Ras and Rac, a small, GTPase binding protein which acts downstream of Ras, by introducing adenoviral vector containing dominant negative Ras and Rac (DN/Ras and DN/Rac) into these cells. Both DN/Ras and DN/Rac reduced the invasive potential of src-transfected cells. Moreover, DN/Rac suppressed completely the tumorigenic potentials of src-transfected cells in nude mice. These results suggest that Src, Ras, Rac, all appeared to participate in the invasion processes, and that Rac may act downstrcam of these signaling pathways of invasion and tumorigenicity. Next we have e … More xamined the effect of activated Src on the sensitivity to taxotere, an anticancer drug targeting microtubules.HAG/src3-1 cells became 7.0-fold sensitive to taxotere. Treatment of HAG/src3-1 cells with taxotere resulted in phosphorylation of Bcl-2 and subsequent induction of apoptotic cell death, whereas neither Bcl-2 phosphorylation nor apoptosis occurred in parental or c-H-ras-transfected HAG-1 cells. Treatment of HAG/src3-1 cells with HA reduced the expression and phosphorylation of Bcl-2, and abrogated taxotere-induced apoptosis, suggesting a potential role for Src tyrosine kinase in the taxotere-induced apoptotic events. These data indicate that the ability of activated Src to increase taxotere sensitivity would be medh~ted by apoptotic events occurring through Src to downstream signal transduction pathways toward Bcl-2 phosphorylation. Finally, we investigated the mechanism of ZD1839-induced growth inhibition and apoptosis in EGFR-expressing HAG-I human gallbladder carcinoma cells. ZD1839 substantially increased the expression of pro-apoptotic Bax proteinwithout affecting the expression of either anti-apoptotic Bcl-2 or pro-apoptotic Bad. Our results indicate that apoptosis induction through activation of Bax would be a novel mechanism for the ZD1839-induced antitumor activity. Less