Retinoids are a group of natural derivatives and synthetic analogs of vitamin A that are required for essential life processes. Many laboratories including our own have shown that retinoids inhibit the growth of a wide variety of tumor cells both in vivo and in vitro. Previous studies from our laboratory have investigated the effect of all-trans-retinoic acid (IRA) on the growth of ovarian carcinoma cells. The growth of the cell line CA-OV3 was found to be inhibited by RA treatment while the growth of SK-OV3 cells was not. Moreover, we showed that RA treatment blocked cell cycle progression during G-1. More recently we set out to identify potential cell cycle gene targets which mediate retinoid dependent growth suppression of ovarian carcinoma cells. Since retinoid inhibited cells are blocked in G-1 we compared the expression and activity of cell cycle genes known to function in the RB pathway in RA sensitive CA-OV3 cells and IRA resistant SK-OV3 cells. IRA treatment of CA-OV3 cells resulted in a significant enhancement in the levels of RB-2/p130 and p27kip1 protein. No comparable increase in RB-2/p130 or p27kip1 was observed in RA treated SK-OV3 cells which are not growth inhibited. Based on these studies we hypothesize that RB-2/p130 and p27 kip1 represent important molecular targets which mediate ovarian carcinoma cell growth suppression by RA. In this application we propose to better understand the mechanism of RB-2/p130 and p27 kip1 protein accumulation by retinoids and thus elucidate the molecular events required for growth arrest mediated by RA. It should be noted that the targeting of RB-2/p130 in ovarian tumor cells as an essential mediator of growth suppression by retinoids is UNIQUE in that all other tumor models exhibit only dephosphorylation of RB and not increased expression of RB-2/p130 upon treatment with retinoids. Clearly the mechanism of retinoid action in ovarian tumor cells is different from that in other models. Thus, study of the mechanism of retinoid inhibition of growth will provide valuable, important information not only on how this potential new chemotherapeutic agent may work but also on the molecular nature of growth regulation in ovarian tumor cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064945-13
Application #
7201609
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Forry, Suzanne L
Project Start
1994-08-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2010-03-31
Support Year
13
Fiscal Year
2007
Total Cost
$249,727
Indirect Cost
Name
Temple University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Purev, Enkhtsetseg; Soprano, Dianne R; Soprano, Kenneth J (2011) PP2A interaction with Rb2/p130 mediates translocation of Rb2/p130 into the nucleus in all-trans retinoic acid-treated ovarian carcinoma cells. J Cell Physiol 226:1027-34
Acquafreda, Thais; Nunes, Fabio Daumas; Soprano, Dianne Robert et al. (2010) Expression of homeobox genes in oral squamous cell carcinoma cell lines treated with all-trans retinoic acid. J Cell Biochem 111:1437-44
Zhao, Jianhua; Zhang, Zhenping; Vucetic, Zivjena et al. (2009) HACE1: A novel repressor of RAR transcriptional activity. J Cell Biochem 107:482-93
Fields, Anthonise Louis; Soprano, Dianne Robert; Soprano, Kenneth J (2008) Characterization of alterations of Rb2/p130 tumor suppressor in all-trans-retinoic acid resistant SK-OV3 ovarian carcinoma cells. J Cell Physiol 217:77-85
Radu, Maria; Soprano, Dianne R; Soprano, Kenneth J (2008) S10 phosphorylation of p27 mediates atRA induced growth arrest in ovarian carcinoma cell lines. J Cell Physiol 217:558-68
Fields, Anthonise Louis; Soprano, Dianne Robert; Soprano, Kenneth J (2007) Retinoids in biological control and cancer. J Cell Biochem 102:886-98
Ravikumar, Sharada; Perez-Liz, Georgina; Del Vale, Luis et al. (2007) Insulin receptor substrate-1 is an important mediator of ovarian cancer cell growth suppression by all-trans retinoic acid. Cancer Res 67:9266-75
Jiang, Tianying; Soprano, Dianne Robert; Soprano, Kenneth J (2007) GADD45A is a mediator of CD437 induced apoptosis in ovarian carcinoma cells. J Cell Physiol 212:771-9
Purev, Enkhtsetseg; Giordano, Antonio; Soprano, Dianne Robert et al. (2006) Interaction of PP2A catalytic subunit with Rb2/p130 is required for all-trans retinoic acid suppression of ovarian carcinoma cell growth. J Cell Physiol 206:495-502
Soprano, K J; Purev, E; Vuocolo, S et al. (2006) Rb2/p130 and protein phosphatase 2A: key mediators of ovarian carcinoma cell growth suppression by all-trans retinoic acid. Oncogene 25:5315-25

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