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.
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