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Down-regulation of increased signal transduction capacity in human cancer cells.

机译:下调人类癌细胞中增加的信号转导能力。

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Signal transduction capacity in human cancer cells is constitutively up-regulated by the markedly increased steady-state activities of the three synthetic enzymes, PI kinase, PIP kinase and PLC, which catalyze the conversion of PI to the second messengers IP3 and DAG. This evidence is supported by the elevated concentration of IP3 in human colon, ovarian and breast carcinoma samples and rat hepatocellular carcinomas and sarcoma. The decrease in activities of the two specific phosphatases in the degradative pathway of signal transduction provides an amplified capacity for IP3 production. The elevated second messenger concentrations should lead to increased calcium release and protein kinase C activation. These biochemical alterations should confer selective biological advantages to cancer cells. The malignancy-linked rise in the activity of the signal transduction pathway can be down-regulated by drugs (tiazofurin, ribavirin, tamoxifen) or through inhibition of the kinases by flavonoids (quercetin, genistein) which lead to a reduction of IP3 concentration. As a result, carcinoma cells in culture stop proliferating and are destroyed. The stringent linkage of signal transduction with neoplasia provides novel targets for clinical chemotherapy.
机译:人体内癌细胞的信号转导能力由三种合成酶(PI激酶,PIP激酶和PLC)的明显增加的稳态活性组成性上调,这些酶催化PI转化为第二信使IP3和DAG。 IP3在人结肠癌,卵巢癌和乳腺癌样本以及大鼠肝细胞癌和肉瘤中的浓度升高支持了这一证据。信号转导降解途径中两种特定磷酸酶活性的降低为IP3的生产提供了增强的能力。第二信使浓度的升高应导致钙释放增加和蛋白激酶C活化。这些生化改变应该赋予癌细胞选择性的生物学优势。可以通过药物(噻唑呋林,利巴韦林,他莫昔芬)或通过类黄酮(槲皮素,染料木黄酮)抑制激酶,从而降低IP3浓度来下调信号转导途径的恶性联系。结果,培养物中的癌细胞停止增殖并被破坏。信号转导与肿瘤形成的严格联系为临床化学疗法提供了新的靶点。

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