Progression of low grade astrocytoma to more aggressive high grade glioblastoma is associated with progressively worse prognosis, and even successful treatment of low grade tumors with conventional chemo- radiotherapy can be associated with debilitating sequellae. Consequently, the need to investigate new and novel approaches for the treatment of brain tumors is necessary. A recent study indicates that most primary human astrocytomas grade I-III (75%) and all glioblastomas tested (100%) express substance P (SP) receptor in the tumor and blood vessel cells. SP peptide induces mitogenesis in various cell types and has angiogenic and vasodialative properties. These established functions for SP peptide may significantly contribute to the progression and growth of brain tumors in vivo by inducing cellular proliferation and increasing blood supply to the tumor. Therefore, the localization of the SP receptor in primary brain tumors, we predict, will have important diagnostic and therapeutic applications. Our data indicate that pediatric and adult astrocytic derived cell lines express a functional SP receptor, and that the SP receptor is mitogenic in astrocytic cells. The central hypothesis to be tested is that at an early stage in the genesis of astrocytic brain tumors, neuropeptides such as substance P activate their receptors and play an important role in triggering the slow growth of low grade astrocytomas (I, II), thus acting as growth promoters. At a later stage of progression of astrocytomas (III), neuropeptides function as growth factors by enhancing tumor growth. In high grade astrocytomas (IV), the growth of the tumor is completely deregulated and becomes unresponsive to neuropeptide growth stimulatory effects possibly due to mutations that constitutively activate receptors. To test this hypothesis we propose the following specific aims: 1) elucidate how the mitogenic SP receptor plays a role in cell growth, using cell lines derived from pediatric and adult astrocytic tumors, 2) determine whether signalling pathways involved in SP induced mitogenesis involve activation of protein kinase C (PKC), 3) determine whether neuropeptide receptor antagonists inhibit growth or induce apoptosis of astrocytic derived cell lines, 4) evaluate conditions of short-term culture that allow determination of the functional status of SP receptor in low grade astrocytoma and normal astrocytes. Our long term objective is to define the role of the mitogenic SP receptor in astrocytic tumors and to investigate blocking this receptor by antagonists as an approach for brain tumor treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Experimental Therapeutics Subcommittee 1 (ET)
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Jacobs, Tom P
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St. Jude Children's Research Hospital
United States
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Sharif, T R; Sasakawa, N; Sharif, M (2001) Regulated expression of a dominant negative protein kinase C epsilon mutant inhibits the proliferation of U-373MG human astrocytoma cells. Int J Mol Med 7:373-80
Sharif, T R; Sharif, M (1999) A high throughput system for the evaluation of protein kinase C inhibitors based on Elk1 transcriptional activation in human astrocytoma cells. Int J Oncol 14:327-35
Sharif, T R; Sharif, M (1999) Overexpression of protein kinase C epsilon in astroglial brain tumor derived cell lines and primary tumor samples. Int J Oncol 15:237-43
Luo, W; Sharif, M (1999) Stable expression of activated Ki-Ras does not constitutively activate the mitogen-activated protein kinase pathway but attenuates epidermal growth factor receptor activation in human astrocytoma cells. Int J Oncol 14:53-62
Sharif, M (1998) Mitogenic signaling by substance P and bombesin-like neuropeptide receptors in astrocytic/glial brain tumor-derived cell lines. Int J Oncol 12:273-86
Sharif, T R; Sharif, M (1998) A novel approach for examining the anti-proliferative effect of protein kinase C inhibitors against human astrocytoma cells. Int J Oncol 13:685-92
Luo, W; Sharif, T R; Houghton, P J et al. (1997) CGP 41251 and tamoxifen selectively inhibit mitogen-activated protein kinase activation and c-Fos phosphoprotein induction by substance P in human astrocytoma cells. Cell Growth Differ 8:1225-40
Sharif, T R; Luo, W; Sharif, M (1997) Functional expression of bombesin receptor in most adult and pediatric human glioblastoma cell lines; role in mitogenesis and in stimulating the mitogen-activated protein kinase pathway. Mol Cell Endocrinol 130:119-30