SIGNAL TRANSDUCTION PATHWAYS COMMITTING SMALL CELL LUNG CARCINOMA TO APOPTOSIS

导致小细胞肺癌凋亡的信号转导途径

• 批准号: 6459539
• 负责人: GARY L JOHNSON
• 金额: $ 6.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6459539
• 关键词: G protein; apoptosis; athymic mouse; biological signal transduction; cell growth regulation; clinical research; human tissue; neuroendocrine system; neuropeptide receptor; protein kinase; small cell lung cancer; substance P; tissue /cell culture; transfection

The objective of this project is to identify the signal transduction pathways which control growth versus apoptosis of lung cancer cells. This information will be used to develop new therapeutic strategies for the prevention and treatment of lung cancer. A focus is given to lung cancers having neuroendocrine properties characteristic of small cell lung carcinoma. Lung cancers having neuroendocrine properties generally express neuropeptides such as gastrin releasing peptide (GRP) and the receptors for neuropeptides. The neuropeptide receptors are seven transmembrane receptors coupled to heterotrimic G proteins generally of the Gq,11 and G12, 13 family. Neuropeptide autocrine and paracrine stimulation of lung cancers having neuroendocrine features stimulate cell growth and proliferation. Studies during the past three years have demonstrated that disruption of neuropeptide autocrine/paracrine signal transduction induces apoptosis, a programmed cell death response of lung cancer cells having neuroendocrine features. Both pharmacologic and genetic disruption of neuropeptide autocrine/paracrine signaling induces apoptosis o small cell lung carcinoma cells. Dissection of signal transduction pathways in small cell lung carcinoma and other cell types indicates that a sequential protein kinase pathway involving the serine/threonine protein kinase referred to as MEK kinase (MEK) regulates apoptosis. This discovery is being used to develop gene therapy strategies for selective expression of activated MEK kinase genes and induciton of apoptosis of lung cancer cells having neuroendocrine properties. In addition, pharmacological strategies are being developed using antagonist peptides that allosterically alter the signaling of neuropeptide receptors to convert a growth stimulatory response to an apoptotic response. The antagonist peptides induce apoptosis by inhibiting specific growth stimulatory responses and activating specific MEK kinase pathways. These studies will be performed with lung cancer cells in culture and also in nude mouse tumor models. In collaboration with other project investigators of the SPORE signal transduction pathways regulating apoptosis of primary human dysplastic lung cells will be defined. Genetic and pharmacological induction of apoptosis will be characterized for lung cell dysplasias. Cumulatively, the in vitro studies to define mechanism and in vivo studies in animals will allow us to design protocols to induce apoptosis of lung cancer cells. Ultimately, these studies will be developed to a point that they can enter human clinical trials

该项目的目标是确定信号转导 控制肺癌细胞生长与凋亡的途径。 这 信息将用于制定新的治疗策略 预防和治疗肺癌。 重点关注肺癌 具有小细胞肺特征的神经内分泌特性 癌。 具有神经内分泌特性的肺癌通常表达 神经肽，例如胃泌素释放肽（GRP）和受体 神经肽。 神经肽受体有七次跨膜 与异源 G 蛋白偶联的受体，通常为 Gq,11 和 G12、13家庭。 神经肽对肺的自分泌和旁分泌刺激 具有神经内分泌特征的癌症会刺激细胞生长 增殖。 过去三年的研究表明 神经肽自分泌/旁分泌信号转导的破坏诱导 细胞凋亡，肺癌细胞的一种程序性细胞死亡反应 神经内分泌特征。 药理学和遗传破坏 神经肽自分泌/旁分泌信号诱导小细胞凋亡 肺癌细胞。 小信号转导途径的剖析 细胞肺癌和其他细胞类型表明连续 涉及丝氨酸/苏氨酸蛋白激酶的蛋白激酶途径 称为MEK激酶（MEK）调节细胞凋亡。 这个发现是 用于开发选择性表达的基因治疗策略 激活MEK激酶基因并诱导肺癌细胞凋亡 具有神经内分泌特性。 此外，药理学策略 正在开发使用拮抗肽来变构改变 神经肽受体的信号传导将生长刺激物转化为 对细胞凋亡反应的反应。 拮抗肽诱导 通过抑制特定的生长刺激反应来凋亡 激活特定的 MEK 激酶途径。 这些研究将进行 培养中的肺癌细胞以及裸鼠肿瘤模型中的肺癌细胞。 在 与 SPORE 信号的其他项目研究人员合作 调节人原发性发育不良肺细胞凋亡的转导途径 单元格将被定义。 细胞凋亡的遗传和药理学诱导 将以肺细胞发育不良为特征。 累计，体外 定义机制的研究和动物体内研究将使我们能够 设计诱导肺癌细胞凋亡的方案。 最终， 这些研究将发展到可以进入人类的程度 临床试验