Ovarian cancer is the leading cause of death among gynecological malignancies and its poor response to current treatments necessitates the development of novel therapeutic or preventive strategies to fight against this deadly disease. Our studies showed that multiple ovarian cancer cell lines responded to 1,25VD for growth suppression. Mechanistic studies suggest that 1,25VD suppresses growth factor signaling, induces cell cycle arrest and promotes apoptosis. Multiple tumor suppressors and oncogenes were identified as being regulated by 1,25VD to mediate these tumor-suppressing activities. More importantly, both in vitro and in vivo studies suggested that synthetic 1.25VD analog EB1089 is a promising drug that can be used to prevent and treat ovarian cancer. Based on these findings, we propose that 1.25VD, through the transcriptional activity of the nuclear vitamin D receptor (VDR), exert a tumor suppressing pathway in ovarian cancer cells; by inducing the expression of tumor suppressors and inhibiting the expression of oncogenes, leading to cell cycle arrest at G1/S and G2/M checkpoints as well as apoptosis. We believe that less calcemic synthetic VD analogues are not only useful drugs for the primary prevention of ovarian cancer, but wiU also premise ovarian cancer patients a new method of treatment. The proposed studies are to substantiate this hypothesis by achieving the following three specific aims:
Aim 1. To test the concept that 1,25VD arrests ovarian cancer cell cycle progression at G1/S checkpoint by inhibiting the cells' response to serum growth factors through the transcriptional down-regulation of the epidermal growth factor receptor;
Aim 2 :To test the concept that the G2/M arrest and apoptosis induced by 1.25VD in ovarian cancer cells are coupled through the induction of GADD45 and to define the steps downstream of GADD45 that mediates the two separale activities of 1,25VD with a focus on the role of p38, Bcl-2 and calpain;
Aim 3. To integrate the information from the molecular studies and, using the mechanistic information, to guide our effort to advance EB1089 for clinical management of ovarian cancer. We believe our studies address an area of research that is under studied and may lead to the development of EB1089 as a novel therapeutic or chemo-preventive drug to treat ovarian cancer. In addition, our studies made many novel findings about the mechanism of 1,25VD action, which may have a much broad impact beyond ovarian cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA111334-02
Application #
7103707
Study Section
Special Emphasis Panel (ZRG1-CDP (01))
Program Officer
Malone, Winfred F
Project Start
2005-08-01
Project End
2010-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$251,681
Indirect Cost
Name
University of South Florida
Department
Pathology
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
Quarni, Waise; Lungchukiet, Panida; Tse, Anfernee et al. (2017) RIPK1 binds to vitamin D receptor and decreases vitamin D-induced growth suppression. J Steroid Biochem Mol Biol 173:157-167
Lungchukiet, Panida; Sun, Yuefeng; Kasiappan, Ravi et al. (2015) Suppression of epithelial ovarian cancer invasion into the omentum by 1?,25-dihydroxyvitamin D3 and its receptor. J Steroid Biochem Mol Biol 148:138-47
Sun, Yuefeng; Sun, Jianwei; Lungchukiet, Panida et al. (2015) Fe65 Suppresses Breast Cancer Cell Migration and Invasion through Tip60 Mediated Cortactin Acetylation. Sci Rep 5:11529
Kasiappan, Ravi; Sun, Yuefeng; Lungchukiet, Panida et al. (2014) Vitamin D suppresses leptin stimulation of cancer growth through microRNA. Cancer Res 74:6194-204
Sun, Yuefeng; Kasiappan, Ravi; Tang, Jinfu et al. (2014) A novel function of the Fe65 neuronal adaptor in estrogen receptor action in breast cancer cells. J Biol Chem 289:12217-31
Kasiappan, Ravi; Shen, Zheng; Tse, Anfernee K-W et al. (2012) 1,25-Dihydroxyvitamin D3 suppresses telomerase expression and human cancer growth through microRNA-498. J Biol Chem 287:41297-309
Shen, Zheng; Zhang, Xiaohui; Tang, Jinfu et al. (2011) The coupling of epidermal growth factor receptor down regulation by 1alpha,25-dihydroxyvitamin D3 to the hormone-induced cell cycle arrest at the G1-S checkpoint in ovarian cancer cells. Mol Cell Endocrinol 338:58-67
Yang, Y; Tse, A K-W; Li, P et al. (2011) Inhibition of androgen receptor activity by histone deacetylase 4 through receptor SUMOylation. Oncogene 30:2207-18
Ma, Qiuping; Fu, Wei; Li, Pengfei et al. (2009) FoxO1 mediates PTEN suppression of androgen receptor N- and C-terminal interactions and coactivator recruitment. Mol Endocrinol 23:213-25
Zhang, Xiaohui; Li, Pengfei; Bao, Junying et al. (2005) Suppression of death receptor-mediated apoptosis by 1,25-dihydroxyvitamin D3 revealed by microarray analysis. J Biol Chem 280:35458-68