Mechanistic Targeting of Lung Cancer

肺癌的机械靶向

• 批准号: 7038520
• 负责人: Lucy M Anderson
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7038520
• 关键词: NAD(P)H dehydrogenase; adenocarcinoma; carcinogenesis; disease /disorder model; gene mutation; laboratory mouse; lung neoplasms; neoplasm /cancer genetics; oncogenes; oxidative stress; peroxides; prostaglandin endoperoxide synthase; redoxin; superoxide dismutase; superoxides

Lung cancer is the most common human neoplasm in the U.S. and, increasingly, in much of the world. While smoking is known to be the major etiological factor, the causative cellular and molecular mechanisms are complex and not well understood. Currently, we are focusing on two aspects of causation and behavior of adenocarcinoma, the most common form of lung cancer: the role of the K-ras gene; and contributions of a signaling pathway triggered by the ErbB3 receptor. The oncogene K-ras is often mutated in adenocarcinoma of the lung (as well as other common carcinomas), but the wild-type form is tumor suppressive. Important questions, then, are: why is mutant K-ras actively oncogenic? How is wild-type K-ras tumor suppressive. Answers to these questions could aid in prevention of up to 50% of human lung adenocarcinomas, and an even higher percentage of cancers of the colon and pancreas. We have found stable transfection of mutant K-ras in lung epithelial cells, with moderate increase in activity, results in upregulation of cyclooxygenase 2, peroxide generation, and DNA damage, which can be blocked with a COX2 inhibitor. Inducible expression of mutant K-ras at high activity leads to generation of both peroxide and superoxides, followed by upregulation of anti-oxidant defenses, especially peroxiredoxins. Abrogation of these defenses by chemicals such as those found in tobacco smoke may lead to cell transformation; this is under test. These results support use of antioxidants for prevention/intervention of lung cancer. Mechanisms of regulation of wild-type K-ras in nontransformed lung epithelial cells are also under study; early results implicate the epidermal growth factor receptor.In the second aspect of this project, the majority of human and mouse lung adenocarcinoma cell lines, but not nontransformed cells, express the ErbB3 receptor, which signals through phosphatidylinositol 3-kinase, Akt, GSK3beta, and cyclin D1 to stimulate the cell cycle and also cell invasiveness and migration. These behaviors can be blocked with siRNA to ErbB3 or the several Akt isoforms. Thiu, siRNA treatment may be an approach to therapy. Tests with xenografts are in progress.

肺癌是美国最常见的人类肿瘤，而且在世界上越来越多。虽然已知吸烟是主要的病因因素，但致病性细胞和分子机制是复杂的，尚不清楚。目前，我们着重于腺癌的因果关系和行为的两个方面，腺癌是肺癌的最常见形式：K-RAS基因的作用； ERBB3受体触发的信号通路的贡献。癌基因K-RAS通常在肺腺癌（以及其他常见的癌）中突变，但野生型形式是抑制肿瘤的。那么，重要的问题是：为什么突变k-ras会主动致癌？野生型K-Ras肿瘤如何抑制。这些问题的答案可以有助于预防多达50％的人类肺腺癌，而结肠和胰腺的癌症比例更高。我们发现在肺上皮细胞中突变K-RAS的稳定转染，活动的增加，导致环氧酶2，过氧化物产生和DNA损伤的上调，可以用COX2抑制剂阻断。突变K-RAS在高活性下的诱导表达可导致过氧化氧化物和超氧化物的产生，然后上调抗氧化剂防御剂，尤其是过氧化物毒素。从烟草烟雾中发现的化学物质（例如烟草烟雾中发现的化学物质）消除这些防御可能会导致细胞转化。这正在进行测试。这些结果支持使用抗氧化剂预防/干预肺癌。非转化的肺上皮细胞中野生型K-RAS调节的机制也正在研究中；早期结果暗示了表皮生长因子受体。在该项目的第二个方面，大多数人和小鼠肺腺癌细胞系，而不是非转化的细胞表达ERBB3受体，该受体通过磷脂酰肌醇3-激酶，AKT，GSK3BETA，GSK3BETA，GSK3BETA，GSK3BETA，，GSK3BETA，，，GSK3BETA，GSK3BETA，，，发出信号。和细胞周期蛋白D1刺激细胞周期以及细胞的侵袭性和迁移。这些行为可以用siRNA对ERBB3或几种AKT同工型阻塞。 Thiu，siRNA治疗可能是一种治疗方法。使用异种移植的测试正在进行中。