Ovarian cancer is the fifth most commonly diagnosed cancer among women and the most frequent cause of death from gynecologic malignancies in the United States. Molecular mechanisms that initiate and support ovarian tumorigenesis are not well defined. We cloned a novel oncogene """"""""PTTG"""""""" also known as securin from human testis and ovarian tumors and studied its function in tumorigenesis. PTTG is a multifunctional protein and is highly expressed in many tumors, including tumors of ovary. Introduction of PTTG into NIH3T3 and HEK293 cells induces cellular transformation and promotes tumor formation in nude mice, suggesting its strong oncogenic function. Notably, PTTG has been shown to inhibit separation of sister chromatids, and to increase the synthesis and secretion of bFGF, VEGF, and IL-8 as well as activate the expression of the oncogene, c-myc and PI3K/AKT signaling pathway, suggesting that the oncogenic activity of PTTG may involve induction of aneuploidy and chromosomal instability, increased angiogenesis, and production of growth promoting oncogene products. Down-regulation of PTTG expression in ovarian tumor cells in vitro and its deletion in animals (Knockout) results in reduction of tumor development, suggesting its important role in maintenance of cancer phenotype. The long-term objectives of this application are to understand the role of PTTG in ovarian tumorigenesis and validate PTTG as a molecular target for the development of anti- neoplastic agents. In this application we propose: i) to determine the effect of overexpression of PTTG in ovarian epithelial cells on cellular transformation and tumor development in nude mice;ii) to determine the effect of overexpression of PTTG in ovarian surface epithelial cells on ovarian tumor initiation, progression and metastasis in transgenic animals and determine mechanisms that support tumor growth and metastasis; and iii)to determine the effect of down-regulation of PTTG expression in ovarian tumor cells on tumor suppression and metastasis and determine mechanisms that lead to suppression of tumor growth and metastasis. These studies will provide critical information regarding the mechanisms of PTTG in ovarian tumorigenesis and metastasis and set up basis for the development of small molecules to inhibit PTTG function as anti-neoplastic agents. In addition transgenic animal model developed from our studies could enhance efforts aimed at developing new methods for detection, prevention, and treatment of ovarian cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA124630-04
Application #
7754388
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2007-03-26
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$253,080
Indirect Cost
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Kakar, Sham S; Parte, Seema; Carter, Kelsey et al. (2017) Withaferin A (WFA) inhibits tumor growth and metastasis by targeting ovarian cancer stem cells. Oncotarget 8:74494-74505
Carter, Kelsey; Rameshwar, Pranela; Ratajczak, Mariusz Z et al. (2017) Verrucarin J inhibits ovarian cancer and targets cancer stem cells. Oncotarget 8:92743-92756
Kakar, Sham S; Worth, Christopher A; Wang, Zhenglong et al. (2016) DOXIL when combined with Withaferin A (WFA) targets ALDH1 positive cancer stem cells in ovarian cancer. J Cancer Stem Cell Res 4:
Kakar, Sham S; Kakar, Cohin (2015) Generation of transgenic mouse model using PTTG as an oncogene. Methods Mol Biol 1267:395-411
Kakar, Sham S; Ratajczak, Mariusz Z; Powell, Karen S et al. (2014) Withaferin a alone and in combination with cisplatin suppresses growth and metastasis of ovarian cancer by targeting putative cancer stem cells. PLoS One 9:e107596
Shah, P P; Fong, M Y; Kakar, S S (2012) PTTG induces EMT through integrin ?V?3-focal adhesion kinase signaling in lung cancer cells. Oncogene 31:3124-35
Kakar, Sham S; Jala, Venkatakrishna R; Fong, Miranda Y (2012) Synergistic cytotoxic action of cisplatin and withaferin A on ovarian cancer cell lines. Biochem Biophys Res Commun 423:819-25
Fong, Miranda Y; Jin, Shunying; Rane, Madhavi et al. (2012) Withaferin A synergizes the therapeutic effect of doxorubicin through ROS-mediated autophagy in ovarian cancer. PLoS One 7:e42265
Fong, Miranda Y; Farghaly, Hanan; Kakar, Sham S (2012) Tumorigenic potential of pituitary tumor transforming gene (PTTG) in vivo investigated using a transgenic mouse model, and effects of cross breeding with p53 (+/-) transgenic mice. BMC Cancer 12:532
Fong, Miranda Y; McDunn, Jonathan; Kakar, Sham S (2011) Identification of metabolites in the normal ovary and their transformation in primary and metastatic ovarian cancer. PLoS One 6:e19963

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