GROWTH INHIBITION BY IL2 OF IL2R+ ORAL CARCINOMAS

IL2 对 IL2R 口腔癌的生长抑制

• 批准号: 2633876
• 负责人: FRANK J JENKINS
• 金额: $ 21.87万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-06-10 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2633876
• 关键词: antisense nucleic acid; apoptosis; athymic mouse; biological signal transduction; cell cycle; cell growth regulation; cell proliferation; confocal scanning microscopy; cyclin dependent kinase; cyclins; cytokine receptors; electron microscopy; enzyme activity; enzyme inhibitors; growth factor receptors; human tissue; interleukin 2; intermolecular interaction; neoplastic cell; neoplastic growth; phosphorylation; receptor expression; retinoblastoma protein; squamous cell carcinoma; tissue /cell culture

DESCRIPTION (Adapted from investigator's Abstract): The application is designed to evaluate the role of the IL-2/IL-2R pathway, found to be ubiquitously expressed in malignant and normal tissues, in growth regulation of oral squamous cell carcinoma (OSCC) cells. The studies completed in the last three years indicate that IL-2 is produced, but not secreted, at levels detectable in ELISA by human OSCC and that it functions as a growth hormone and apoptosis protection factor in tumor cells. These cells also express functional IL-2R. Exogenous IL-2 binding at nM concentrations to its receptor inhibits growth of OSCC cell lines by inducing cell cycle arrest in G0/G1. The mechanisms responsible for growth-promoting signals mediated by endogenous IL-2 vs. negative growth signals delivered by exogenous IL-2 will be investigated in vitro and in vivo, using both OSCC cell lines and xenograft model of OSCC immunosuppressed BALB/c nude mice established in the Prinicpal Investigator's laboratory. They hypothesis to be tested is that endogenous IL-2 acts as growth-promoting factor in OSCC cells by down- regulating expression of CDK cell cycle inhibitors, while exogenous IL-2 interferes with growth by disrupting this essential endogenous pathway. Expression, activity and transcriptional regulation of Cyclins, CDKs and CDK inhibitors and Rb protein phosphorylation levels in OSCC cells treated with antisense IL-2 or antisense IL-2Rbeta and in untreated control cells will be evaluated and related to growth in vivo in OSCC- xenografted nude mice. Mechanisms of IL-2 mediated protection of tumor cells from apoptosis possibly by regulation of the state of Rb protein phosphorylation will be probed. Intracellular pathways of IL-2 mediated protection of tumor cells from apoptosis possibly by regulation of the stat of Rb protein phosphorylation will be probed. Intracellular pathways of IL-2 and IL-2r processing, localization and trafficking in tumor cells will be studied by confocal and immunogold electron microscopy to determine whether exogenous vs. endogenous IL-2 pathways operate in distinct cellular compartments. Understanding of the regulatory role of the IL-2/IL-2R pathway in tumor cells provides opportunities for novel therapeutic interventions in OSCC based not only on arrest of tumor growth by exogenous IL-2 but also on the use of pharmacologic and/or biologic agents known to be able to disrupt the IL- 2 pathway.

描述（改编自研究者摘要）：该应用程序是 旨在评估IL-2/IL-2 R通路的作用，发现 在恶性和正常组织中广泛表达， 口腔鳞状细胞癌（OSCC）细胞的调控。 研究 在过去三年中完成的研究表明，IL-2是生产的，但 不分泌，在ELISA中可检测到的水平，由人类OSCC，它 在肿瘤中作为生长激素和凋亡保护因子发挥作用 细胞 这些细胞还表达功能性IL-2 R。 外源性IL-2 在nM浓度下与其受体结合抑制OSCC生长 细胞周期阻滞在G 0/G1期。 的机制 负责内源性IL-2介导的生长促进信号， 将研究外源性IL-2传递的负生长信号 在体外和体内，使用OSCC细胞系和异种移植模型， 口腔鳞癌免疫抑制BALB/c裸鼠模型的建立 调查员实验室 他们要检验的假设是， 内源性IL-2通过下调- 调节CDK细胞周期抑制因子的表达，而外源性IL-2 通过破坏这种基本的内源性途径来干扰生长。 细胞周期蛋白、细胞周期蛋白激酶和细胞周期蛋白激酶的表达、活性和转录调控 口腔鳞癌细胞中CDK抑制剂和Rb蛋白磷酸化水平的研究 用反义IL-2或反义IL-2 R β治疗， 将评价对照细胞并将其与OSCC中的体内生长相关。 异种移植裸鼠。 IL-2介导的肿瘤保护机制 可能通过调节Rb蛋白的状态而使细胞免于凋亡 将探测磷酸化。 IL-2介导的细胞内途径 保护肿瘤细胞免于凋亡可能是通过调节 将探测Rb蛋白磷酸化状态。 细胞内 IL-2和IL-2 r的加工、定位和运输途径 肿瘤细胞将通过共聚焦和免疫金电子显微镜进行研究。 显微镜检查，以确定外源性与内源性IL-2途径 在不同的细胞区室中运作。 理解 IL-2/IL-2 R通路在肿瘤细胞中的调节作用提供了 OSCC的新型治疗干预的机会不仅基于 通过外源性IL-2抑制肿瘤生长， 已知能够破坏IL-1的药理学和/或生物学试剂， 2路。