GLUTAMINE AND BREAST CANCER PROLIFERATION AND TREATMENT

谷氨酰胺是一种重要的营养素， 培养的哺乳动物细胞和肿瘤细胞对谷氨酰胺 消费者 然而，人们对这种机制知之甚少， 谷氨酰胺支持肿瘤细胞增殖和存活力。 这个修订 应用程序将测试谷氨酰胺提供 肿瘤细胞与还原当量以及前体， 谷胱甘肽合成，一种对细胞生长至关重要的分子， 保护免受化学和氧化损伤。 谷氨酰胺利用 可能有助于细胞的氧化还原代谢和机制， 细胞对氧化和异生素应激作出反应。 一系列表现出广泛谷氨酰胺的人乳腺细胞系 对生长和生存能力的依赖，以及广泛的 谷氨酰胺利用率，已经确定。 此外该 两种高谷氨酰胺敏感乳腺细胞系对 谷氨酰胺饥饿已被表征，并将用于直接 测试一些假设：1）谷氨酰胺是用来提供谷氨酸 和胱氨酸合成谷胱甘肽。2)谷氨酰胺利用 为肿瘤细胞线粒体提供还原等价物， 通过线粒体氧化还原控制肿瘤细胞的生长和生存能力 机制等3)靶向抑制谷氨酰胺酶表达， 参与谷氨酰胺分解的酶，抑制谷氨酰胺利用， 从而抑制生长并增加肿瘤细胞对 通过谷胱甘肽解毒的化疗药物。 总的来说， 将开发阻断肿瘤细胞利用谷氨酰胺的方法， 以及该策略抑制肿瘤生长或 增加肿瘤对化学毒性药物的敏感性， 考察这可能为新的代谢导向的 癌症治疗

Glutamine is an essential nutrient for the growth and maintenance of mammalian cells in culture, and tumor cells are avid glutamine consumers. However, little is known about the mechanism by which glutamine supports tumor cell proliferation and viability. This revised application will test the overall hypothesis that glutamine provides tumor cells with reductive equivalents as well as precursors for glutathione synthesis, a molecule which is essential for cellular protection against chemical and oxidative damage. Glutamine utilization may contribute to cellular redox metabolism and the mechanism by which cells respond to oxidative and xenobiotic stress. A series of human breast cell lines exhibiting a wide range of glutamine dependence for growth and viability, as well as a wide range of glutamine utilization rates, have been identified. In addition, the response of two highly glutamine-sensitive breast cell lines to glutamine starvation has been characterized and will be used to directly test a number of hypotheses: 1) Glutamine is-used to provide glutamate and cystine for synthesis of glutathione. 2) Glutamine utilization provides reductive equivalents to tumor cell mitochondria and therefore controls tumor cell growth and viability through mitochondrial redox mechanisms. 3) Targeted inhibition of glutaminase expression, the first enzyme involved in glutaminolysis, represses glutamine utilization and thereby inhibits growth and increases the sensitivity of tumor cells to chemotherapeutic drugs which are detoxified by glutathione. In general, methods to block the use of glutamine by tumor cells will be developed, and the efficacy of this strategy for inhibiting tumor growth or for increasing the sensitivity of tumors to chemotoxic drugs will be examined. This may provide the basis for novel metabolically directed cancer therapies.