Lysophosphatidic acid (LPA), a naturally occurring phospholipid, activates distinct members of the endothelial differentiation gene subfamily of G protein-coupled receptors to elicit multiple cellular responses. LPA was first implicated in ovarian cancer by the observation that LPA is present at elevated levels in ascites of ovarian cancer patients. LPA stimulates proliferation, survival, drug resistance and motility of ovarian cancer cells. However, the exact role of LPA in ovarian oncogenesis, particularly in vivo, remains poorly understood. We have recently performed cDNA microarrays to determine the profile of LPA-induced and repressed genes in ovarian cancer cells. One of the most striking changes induced by LPA was the dramatic induction of pro-angiogenic factors including interleukin 6 (IL-6), interleukin 8 (IL-8), growth-related oncogene a (GROa) and vascular endothelial growth factor (VEGF), suggesting that angiogenic factors are major target genes of LPA in ovarian cancer cells. These LPA-induced factors are important mediators of angiogenesis, tumorigenicity and cancer progression. In particular, high serum levels of IL-6 and IL-8 in ovarian cancer patients correlate with poor response to chemotherapy and poor prognosis. We hypothesize that LPA stimulation of angiogenic factor expression and neovascularization contributes to the pathogenesis of ovarian cancer. The hypothesis will be examined through 3 specific aims: A) To elucidate the mechanism by which LPA induces production of pro-angiogenic factors; B) To examine the role of LPA in the regulation of angiogenic factor expression in ovarian cancer cells; and C) To determine the role of LPA in neovascularization. LPA receptors and the intracellular signaling networks that link LPA to expression of angiogenic factors will be identified in ovarian cancer cells. We will then examine whether LPA is a primary endogenous regulator of angiogenic factor expression in ovarian cancer cells. The potential angiogenic activity of LPA will be studied by in vivo angiogenesis assay and in nude mouse xenograft models. These studies will improve our understanding of ovarian carcinogenesis and will potentially lead to a novel therapy targeting LPA receptors and LPA production. As a small phospholipid molecule, LPA signals through G protein-coupled receptors that are highly """"""""drugable"""""""" molecules. More than half of all drugs in current use target this large family of cell surface receptors. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA102196-03
Application #
7104837
Study Section
Special Emphasis Panel (ZRG1-TME (01))
Program Officer
Woodhouse, Elizabeth
Project Start
2004-08-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$225,946
Indirect Cost
Name
Virginia Commonwealth University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Wu, J; Mukherjee, A; Lebman, D A et al. (2013) Gene expression of the lysophosphatidic acid receptor 1 is a target of transforming growth factor beta. Oncogene 32:3198-206
Mukherjee, Abir; Wu, Jinhua; Barbour, Suzanne et al. (2012) Lysophosphatidic acid activates lipogenic pathways and de novo lipid synthesis in ovarian cancer cells. J Biol Chem 287:24990-5000
Van, Danielle N; Roberts, Charlotte F; Marion, James D et al. (2012) Innate immune agonist, dsRNA, induces apoptosis in ovarian cancer cells and enhances the potency of cytotoxic chemotherapeutics. FASEB J 26:3188-98
Wijesinghe, Dayanjan S; Mayton, Eric K; Mietla, Jennifer A et al. (2011) Characterization of lysophosphatidic acid subspecies produced by autotaxin using a modified HPLC ESI-MS/MS method. Anal Methods 3:2822-2828
Wu, Jinhua; Mukherjee, Abir; Lebman, Deborah A et al. (2011) Lysophosphatidic acid-induced p21Waf1 expression mediates the cytostatic response of breast and ovarian cancer cells to TGF?. Mol Cancer Res 9:1562-70
Song, Yuanda; Dilger, Emily; Bell, Jessica et al. (2010) Large scale purification and characterization of recombinant human autotaxin/lysophospholipase D from mammalian cells. BMB Rep 43:541-6
Oyesanya, Regina A; Greenbaum, Susie; Dang, David et al. (2010) Differential requirement of the epidermal growth factor receptor for G protein-mediated activation of transcription factors by lysophosphatidic acid. Mol Cancer 9:8
Ramachandran, Subramaniam; Shida, Dai; Nagahashi, Masayuki et al. (2010) Lysophosphatidic acid stimulates gastric cancer cell proliferation via ERK1-dependent upregulation of sphingosine kinase 1 transcription. FEBS Lett 584:4077-82
Song, Yuanda; Wu, Jinhua; Oyesanya, Regina A et al. (2009) Sp-1 and c-Myc mediate lysophosphatidic acid-induced expression of vascular endothelial growth factor in ovarian cancer cells via a hypoxia-inducible factor-1-independent mechanism. Clin Cancer Res 15:492-501

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