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Project Title: Role of prostanoid receptors in tumorigenesis and radiation resistance
Principal Investigator: Chaitanya Nirodi
Institution: UT Southwestern Medical Center, Dallas, Texas.
Department: Radiation Oncology
Mail code: 9183
Phone: (214)-648-7318
E-mail: Chaitanya.Nirodi@UTSouthwestern.edu

Description: Prostaglandins are derived from cyclooxygenase mediated oxygenation of arachidonic acid and play important roles in diverse physiological processes. Levels of the inducible cyclooxygenase isoform, COX-2, are elevated in cancers of the colon, breast, prostate, lung and skin. Moreover, cellular responses to ionizing radiation involve induction of COX-2 gene expression suggesting a role for COX-2 metabolism in cell survival in radiation resistant cancer cells.
Constitutive expression of COX-2 in tumors and radiation resistant cells has been associated with striking increases in the levels of the dominant prostaglandin E2 (PGE2). In cell culture and tumor models, PGE2 has been shown to stimulate cell proliferation, cell motility, cell survival and angiogenesis. The mechanisms underlying PGE2 stimulated cell proliferation are not completely understood.
PGE2 exerts its effects on cell function through specific G-protein coupled receptors, classified into four basic subtypes EP1, EP2, EP3, and EP4. The receptors show significant differences in structure, specificity to the subunit isoform of the trimeric G-protein, and activation of downstream signaling pathways. The EP4 receptor exhibits considerable heterogeneity in physiological function. In varying physiological settings, ligand stimulated EP4 receptor is coupled to (a) activation of adenylate cyclase, (b) activation of cell survival pathways involving phosphatidyl inositol 3 kinase, PI3K, and protein kinase B/AKT and (c) transactivation of the EGF receptor tyrosine kinase. The molecular mechanism by which the EP4 receptor transactivates EGFR is not clearly understood.
The objective of this investigation will be to elucidate the role of a pro-inflammatory stimulus, PGE2, in (1) colon cancer and (2) acquisition of radiation resistance. The study will be based on the hypothesis that during carcinogenesis and development of resistance to ionizing radiation, PGE2 transactivates the epidermal growth factor by signaling through a heterodimeric receptor complex containing the EP4 receptor and either a second EP receptor subtype or an oncogenic G-protein coupled receptor.

Selected Publications
1. Nirodi, C. et al. A role for poly(ADP-ribose) polymerase in the transcriptional regulation of the melanoma growth stimulatory activity (CXCL1) gene expression. J Biol Chem 276, 9366-74 (2001).
2. Nirodi, C. et al. The role of CDP in the negative regulation of CXCL1 gene expression. J Biol Chem 276, 26122-31 (2001).
3. Nirodi, C.S., Crews, B.C., Kozak, K.R., Morrow, J.D. & Marnett, L.J. The glyceryl ester of prostaglandin E2 mobilizes calcium and activates signal transduction in RAW264.7 cells. Proc Natl Acad Sci U S A 101, 1840-5 (2004).

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