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

基本信息

批准号：
7085330
负责人：
ISA M HUSSAINI
金额：
$ 24.03万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
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

项目摘要

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（申请人提供）：恶性星形胶质瘤患者的预后很差。星形细胞瘤既能侵入邻近的大脑部位，又能迁移到远处的大脑部位，因此无法进行根治性手术切除；在设计显着影响长期生存的辅助疗法方面进展甚微。为了制定更新颖的治疗策略，有必要更好地了解如何控制这些肿瘤的侵袭性生长。我们实验室使用两种具有独特生长模式的人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。在 PKC-eta 缺陷的 U-1242 MG 细胞中过度表达该酶将对佛波酯的反应从生长抑制转变为增殖。 PKC-eta 反义寡核苷酸和 cDNA 构建体抵消了对 PMA 的反应，表明 PKC-eta 可能参与有丝分裂反应。该提案的重点是了解恶性星形胶质细胞与非肿瘤性星形胶质细胞之间 PKC-eta 激活和表达的差异，以及 PKC-eta 在控制细胞增殖和凋亡的信号通路中的作用。恶性星形细胞肿瘤中细胞增殖和侵袭性细胞生长的调节无疑是复杂的；然而，可以利用这些过程的 PKC-eta 调节来提供可以选择性诱导和研究增殖和凋亡表型的实验系统。如果非肿瘤性和恶性星形胶质细胞通过特定的 PKC-亚型对增殖具有不同的调节，并且如果培养细胞的生物学行为可以外推到我们的动物模型，那么 PKC-eta 的药理调节与靶向细胞迁移的药物相结合，可能会产生不同的增殖调节。为这些侵袭性脑肿瘤提供了一种新的治疗范例。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。该资助的第一个目标（目标 I 和 2）是确定 PKC-eta 的表达和激活在星形胶质细胞肿瘤细胞和非肿瘤性星形胶质细胞中是否受到不同的控制。第二个目标（目标 3）是（a）确定 PKC-eta 的过度表达或缺乏是否会影响星形细胞肿瘤的生长和凋亡，（b）确定介导这些反应的 PKC-eta 下游的信号传导通路，最后（c）测试细胞培养数据是否模拟体内肿瘤生物学。这将在动物星形细胞肿瘤模型中进行测试。了解特定 PKC 同工酶在星形细胞肿瘤生长和凋亡中的作用将为治疗干预的可能特定靶标提供信息。