Role of PKCeta in Regulating Astrocytoma Invasive Growth

PKCeta 在调节星形细胞瘤侵袭性生长中的作用

• 批准号: 6911640
• 负责人: ISA M HUSSAINI
• 金额: $ 24.61万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6911640
• 关键词: SCID mouse; antisense nucleic acid; apoptosis; astrocytes; astrocytoma; biological signal transduction; cell growth regulation; cell line; cell proliferation; clinical research; enzyme activity; gene expression; genetic promoter element; human tissue; immunocytochemistry; in situ hybridization; isozymes; laboratory rat; magnetic resonance imaging; messenger RNA; neoplastic growth; northern blottings; protein kinase C; tissue /cell culture; transcription factor; tumor promoters

DESCRIPTION (provided by applicant): The prognosis for patients with malignant astroglial tumors is poor. The capacity of astrocytomas both to invade adjacent and to migrate into distant brain sites precludes curative surgical resection; and little progress has been made in designing adjuvant therapies that significantly affect long-term survival. In order to formulate more novel therapeutic strategies, it is essential to have a better understanding of how the invasive growth of these tumors is controlled. Recent data from our laboratory using two human glioblastoma cell lines with distinctive growth patterns demonstrate a correlation between expression of protein kinase C-eta (PKC-eta) and a PMA-induced increase in proliferation and decrease in migration. Over-expression of the enzyme in PKC-eta-deficient U-1242 MG cells converted the response to phorbol ester from growth inhibition to proliferation. PKC-eta antisense oligonucleotide and cDNA construct counteracted the response to PMA, suggesting that PKC-eta may be involved in the mitogenic response. This proposal is focused on understanding differences in PKC-eta activation and expression between malignant vs. non-neoplastic astrocytes and on the role of PKC-eta in signaling pathways that control cell proliferation and apoptosis. The regulation of cell proliferation and invasive cell growth in malignant astrocytic tumors is undoubtedly complex; however, the PKC-eta regulation of these processes may be exploited to provide an experimental system in which proliferative and apoptotic phenotypes may be selectively induced and studied. If non-neoplastic and malignant astrocytes have differential regulation of proliferation by specific PKC-isoforms, and if the biologic behavior of the cultured cells can be extrapolated to our animal model, pharmacological regulation of PKC-eta in combination with drugs targeting cellular migration, may present a new therapeutic paradigm for these aggressive brain tumors. I hypothesize that: Expression and activation of PKC-eta are critical in regulating proliferation and apoptosis in astrocytic tumors. The first goal (Aims I &2) of this grant is to determine whether expression and activation of PKC-eta are controlled differently in astrocytic tumor cells and non-neoplastic astrocytes. The second goal (Aim 3) is to (a) determine whether over-expression or deficiency of PKC-eta affects astrocytic tumor growth and apoptosis, (b) identify signaling pathways downstream of PKC-eta mediating these responses, and finally (c) test whether the cell culture data model the in vivo tumor biology. This will be tested in an animal astrocytic tumor model. Understanding the roles of specific PKC isozymes in growth and apoptosis of astrocytic tumors will provide information on possible specific targets for therapeutic intervention.

描述（由申请人提供）：恶性星形胶质肿瘤患者的预后很差。星形胶质细胞瘤入侵邻近和迁移到远处的大脑部位的能力排除了治疗手术切除；在设计显着影响长期生存的辅助疗法方面，几乎没有取得进展。为了制定更新颖的治疗策略，必须更好地了解如何控制这些肿瘤的侵入性生长。使用两个具有独特生长模式的人类胶质母细胞瘤细胞系的最新数据表明，蛋白激酶C-ETA（PKC-ETA）的表达与PMA诱导的增殖增加和迁移减少之间存在相关性。 PKC-ETA缺陷型U-1242 mg细胞中酶的过表达将对佛波酯的反应从生长抑制转化为增殖。 PKC-ETA反义寡核苷酸和cDNA构建体抵消了对PMA的反应，这表明PKC-ETA可能与有丝分裂反应有关。该建议的重点是理解PKC-ETA激活与非肿瘤星形胶质细胞之间的差异以及PKC-ETA在控制细胞增殖和凋亡的信号通路中的作用。恶性星形肿瘤中细胞增殖和浸润性细胞生长的调节无疑是复杂的。但是，可以利用这些过程的PKC-ETA调节以提供实验系统，在该系统中可以选择性地诱导和研究增生和凋亡表型。如果非肿瘤和恶性星形胶质细胞对特定的PKC-异型型对增殖具有差异性调节，并且如果可以将培养细胞的生物学行为外推到我们的动物模型中，则PKC-ETA的药理调节，与靶向细胞迁移的药物相结合，可能会出现新的治疗性寄生虫，以表现出这些新的帕拉德式帕拉德式甲虫。我假设：PKC-ETA的表达和激活对于调节星形细胞肿瘤的增殖和凋亡至关重要。该赠款的第一个目标（目标I＆2）是确定PKC-ETA的表达和激活是否在星形细胞肿瘤细胞和非肿瘤性星形胶质细胞中受到不同的控制。第二个目标（AIM 3）是（a）确定PKC-ETA的过表达或缺乏影响星形胶质性肿瘤的生长和凋亡，（b）确定PKC-ETA下游介导这些反应的信号通路，以及（最终（C）测试细胞培养数据模型是否在体内肿瘤生物学。这将在动物星形肿瘤模型中进行测试。了解特定PKC同工酶在生长和星形胶质细胞凋亡中的作用将提供有关治疗干预可能的特定靶标的信息。