There is compelling evidence for the reduction of the incidense and severity of cancers associated with the use of non steroidal anti-inflammatory drugs. We investigated the cellular and gene expression pattern changes following the in vitro application of two NSAIDs, diclofenac and indomethacin on several ovarian cancer cell lines and in vivo after administration in a xenograph model. We saw a reduction in the number of viable cells due to an increase in apoptosis and cell cycle arrest. After illumina microarray analysis, E2F1 was found to be a target. Since ovarian cancer cells over express claudins-3 and -4, we decided to investigate the possibility of using CPE, an enterotoxin known to function via these two tight junction proteins, as a potential therapeutic. In vitro assays were set up utilizing several ovca cell lines with varying claudin expression patturns. While indeed cells that expressed claudin-3 and -4 did experience a market reduction in viability, it was discovered that those cells that expressed caludin 6 were also targeted. This represented a novel receptor for the enterotoxin. Speroids created with claudin-6 expressing cells, also confirmed this novel finding.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000395-06
Application #
8736558
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$902,167
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Valle, Blanca L; D'Souza, Theresa; Becker, Kevin G et al. (2013) Non-steroidal anti-inflammatory drugs decrease E2F1 expression and inhibit cell growth in ovarian cancer cells. PLoS One 8:e61836
D'Souza, Theresa; Sherman-Baust, Cheryl A; Poosala, Suresh et al. (2009) Age-related changes of claudin expression in mouse liver, kidney, and pancreas. J Gerontol A Biol Sci Med Sci 64:1146-53
Li, Jianghong; Chigurupati, Srinivasulu; Agarwal, Rachana et al. (2009) Possible angiogenic roles for claudin-4 in ovarian cancer. Cancer Biol Ther 8:1806-14
Li, Jianghong; Sherman-Baust, Cheryl A; Tsai-Turton, Miyun et al. (2009) Claudin-containing exosomes in the peripheral circulation of women with ovarian cancer. BMC Cancer 9:244
Lal-Nag, Madhu; Morin, Patrice J (2009) The claudins. Genome Biol 10:235
Choi, Jung-Hye; Park, Joon T; Davidson, Ben et al. (2008) Jagged-1 and Notch3 juxtacrine loop regulates ovarian tumor growth and adhesion. Cancer Res 68:5716-23