FA 5 Progress Report WV-INBRE - Joan C. Edwards School of ...

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Program Director/Principal Investigator (Last, First, Middle): Rankin, Gary O 44PI3K, AKT AND ERR-ALPHA PATHWAYS IN FLAVONOID-INHIBITING TUMORIGENESIS(0032)TYPE:Research Subproject%IDeA $: 4.000% IDeA $: 125,000INVESTIGATOR, DEGREEChen, Yi C PHDLuo, Haitao PHDRojanasakul, Yon PHDDEPARTMENTBiologyBiologyBaic PharmaceuticalSciencesNON-HOST INSTITUTION: STATE,COUNTRYAlderson-Broaddus College, Wv UsaAlderson-Broaddus College, Wv UsaWest Virginia University, Wv UsaTotal # human subjects expected for entire study: 0Total # human subjects enrolled to date: 0SUBPROJECT DESCRIPTIONIn this study, we tend to expand our understanding on the effect of flavonoid kaempferol and how kaempferolregulates VEGF expression and angiogenesis in ovarian cancer cells. We timed VEGF secretion, andstudied in-vitro angiogenesis by kaempferol treatment. Gene expression was examined by qRT-PCR,ELISA, Western Blotting, or luciferase assay, and pathways were examined by manipulating geneticcomponents with plasmid or siRNA transfection. It was found that kaempferol time-dependently inhibitedVEGF secretion, and suppressed in-vitro angiogenesis. Kaempferol down-regulated ERK phosphorelationas well as NFkappaB and cMyc expression, but promoted p21 expression. Examination of relationshipbetween these genes suggested a novel ERK-NFkappaB-cMyc-p21-VEGF pathway, which accounts forkaempferol’s angioprevention effects in ovarian cancer cells. These data supplements our comprehensionof the mechanisms behind kaempferol’s biological influence in ovarian cancer cells, and bettercharacterized kaempferol toward chemoprevention.SUBPROJECT PROGRESSWe have successfully completed these specific aims proposed in our previous proposal.Aim 1. Identify the roles and molecular mechanisms of flavonoids in inhibiting EGFR, PI3K, AKT,and ERRα in ovarian cancer cells. We found that the flavonoid kaempferol inhibited PI3K/AKT,and ERRα regulated VEGF expression in ovarian cancer cells. We published our results inpeer-reviewed scientific journals.Aim 2. Determine flavonoid-inhibiting signaling pathways that affect ovarian tumor growth. Wefound that both HIF dependent (PI3K/AKT) pathway and HIF independent (ERRα and cMyc)pathways were involved in the ovarian tumor growth inhibition. We published our results inpeer-reviewed scientific journals.Aim 3. Determine whether kaempferol inhibit ovarian tumor angiogenesis, and identify whichsignaling molecules mediate kaempferol-inhibiting tumor angiogenesis. We found that kaempferolinhibit ovarian tumor angiogenesis through inhibiting HIF-1α, VEGF, cMyc and ERRα signalingmolecules. We published our results in peer-reviewed scientific journals.PROTECTION AGAINST RESEARCH RISKSN 1. Will human subjects be involved next year?N 2. Will vertebrate animals be used next year?N 3. Will recombinant DNA experiment(s) be conducted next year?N 4. Are there potential hazards to laboratory workers (carcinogens, pathogens, ionizing radiation, etc.)involved in the proposed research for next year? If yes, identify:N5. Will any of the research-risk categories,not involved next year, be involved future years? If yes, identify:PHS 2590 (Rev. 06/09)Continuation Format Page
Program Director/Principal Investigator (Last, First, Middle): Rankin, Gary O 45SEX STEROID HORMONES AND EPIGENETICS IN MENINGIOMAS (0038)TYPE: Research Subproject%IDeA $: 5.000% IDeA $: 174,407INVESTIGATOR, DEGREEHankins, Gerald PHDDEPARTMENTBiologyNON-HOST INSTITUTION: STATE,COUNTRYWest Virginia State University, Wv UsaTotal # human subjects expected for entire study: 0Total # human subjects enrolled to date: 0SUBPROJECT DESCRIPTIONMeningiomas comprine approximately 30% of primary central nervous system tumors in the United States,however their pathobiology is poorly understood. Over 90% of meningiomas are benign while 5% areatypical and 3-5% are malignant. Complete surgical resection is the treatment of choice for benignmeningiomas. Surgical resection is often difficult since approximately one-half of benign intracranialmeningiomas arise in the skull base. For skull base meningiomas the surgical complication rate can be ashigh as 30 to 40% even in expert hands. The female to male incidence ratio in adults is 2:1 for intracranialtumors and 10:1 for spinal tumors, while no such sex difference exists for meningiomas in children.Therefore, the female sex steroid hormones progesterone and -estradiol are suspected factors inmeningioma tumorigenesis. However, no mechanisms have been demonstrated for female sex hormonesinmeningioma formation or progression. We recently reported evidence that a steroid responsive gene,deleted in liver cancer-1 (DLC1), may function as a tumor suppressor in meningiomas. Our microarray dataindicate that a number of steroid responsive genes are differentially expressed between meningiomas andnormal meninges. We also found that steroid hormones and their antagonists can alter the growth ofmeningioma cells and that histone deacetylase inhibitors induce a decrease of meningioma cell growth inculture. Our long-term goal is to develop strategies to prevent or slow meningioma tumor growth that canserve as alternatives or adjuncts to surgery. The central hypotheses of this study are 1) that meningiomatumorigenesis is driven in part by actions of female steroid hormones and 2) that the tumorrigenesis may bemediated in part by progesterone and estrogen receptor containing chromatin-modifying complexes. Wepropose to test our hypothesis by pursuing the following three specific aims:1) To treat meningioma cells with progesterone or 17β-estradiol and assess the expression of severalgenes that are differentially regulated between meningiomas and normal meninges.2) To evaluate the effects of inhibitors of DNA methylation or histone de-acetylation on the growth ofmeningioma cells in vitro and on expression of genes that are differentially expressed betweenmeningiomas and normal meninges.3) To determine whether the promoters of the differentially regulated genes in specific aim 1 and 2 arebound by progesterone receptor, estrogen receptor, ETS2, or the histone acetyltransferase p300.1) To treat meningioma cells with progesterone or 17 -estradiol and assess the expression of severalgenes that are differentially regulated between meningiomas and normal meninges.2) To evaluate the effects of inhibitors of DNA methylation or histone de-acetylation on the growth ofmeningioma cells in vitro and on expression of genes that are differentially expressed betweenmeningiomas and normal meninges.3) To determine whether the promoters of the differentially regulated genes in specific aim 1 and 2 arebound by progesterone receptor, estrogen receptor, ETS2, or the histone acetyltransferase p300.SUBPROJECT PROGRESSDuring the past year we have focused on specific aims 1 and 2.One graduate student and an undergraduate student have focused on fibroblast growth factorsPHS 2590 (Rev. 06/09)Continuation Format Page
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