title: Src tyrosine kinase but not activated Ras augments sensitivity to taxanes through apoptosis in human adenocarcinoma cells.
abstract: We investigated the mechanistic role of Src and Ras, important oncoproteins implicated in the pathogenesis of many human cancers, in taxane-induced apoptosis using v-src or c-H-ras transfected HAG-1 human gallbladder epithelial cells. Compared with the parental HAG-1 cell line, v-src-transfected HAG/src3-1 cells became 6.0-fold and 7.5-fold sensitive to taxotere, and 1.8-fold and 3.9-fold sensitive to taxol, for 2-hour and 24-hour exposures, respectively. By contrast, HAG-1 cells transfected with activated Ras, which acts downstream of Src, acquired approximately 2.7- and 5.0-fold taxotere resistance, and 2.3- and 2.8-fold taxol resistance, for both exposures, respectively. To examine the mechanism(s) whereby Src augments sensitivity to taxanes, we investigated the functional role of Src in taxotere-induced apoptosis. Treatment of HAG/src3-1 cells with taxotere resulted in subsequent induction of apoptotic cell death, whereas apoptosis did not occur in parental or c-H-ras-transfected HAG/ras5-1 cells. Moreover, a protein kinase C (PKC) and a phosphatidylinositol-3 kinase (PI-3 kinase) inhibitors (H-7 and wortmannin, respectively) did not alter either taxotere sensitivity or taxotere-induced apoptosis in these cells. Similarly, non-cytotoxic concentrations of geldanamycin, which destabilizes c-Raf-1 kinase, did not prevent apoptosis in HAG/src3-1 cells. These data indicate that the ability of activated Src to sensitize HAG/src3-1 cells to taxotere might be mediated by apoptotic events occurring through Src to downstream signal transduction pathways, excluding activated Ras, Raf-1 kinase, PI-3 kinase and PKC.
authors.affiliation: Department of Medicine and Biosystemic Science, Graduate School of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Boudny
authors.forename: Shuji
authors.initials: S
authors.lastname: Nakano
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D016227:Benzoquinones; D000077143:Docetaxel; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011905:Genes, ras / Q000235:genetics; D016391:Genes, src / Q000235:genetics; D006801:Humans; D047029:Lactams, Macrocyclic; D015688:Oncogene Protein pp60(v-src) / Q000502:physiology*; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D043823:Taxoids; D014162:Transfection; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000502:physiology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016227:Benzoquinones; D000077143:Docetaxel; D047029:Lactams, Macrocyclic; D015688:Oncogene Protein pp60(v-src); D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D011809:Quinones; D017828:Rifabutin; D043823:Taxoids; D018631:ras Proteins; C020754:herbimycin; C001277:geldanamycin