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Carcinogenesis Advance Access originally published online on July 29, 2008
Carcinogenesis 2008 29(10):1893-1900; doi:10.1093/carcin/bgn158
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Tissue transglutaminase protects epithelial ovarian cancer cells from cisplatin-induced apoptosis by promoting cell survival signaling

Liyun Cao1,5, Daniela N. Petrusca1, Minati Satpathy1, Harikrishna Nakshatri2,3,4,5, Irina Petrache1,5 and Daniela Matei1,3,4,5,6,7,*

1 Department of Medicine
2 Department of Surgery
3 Melvin and Bren Simon Cancer Center
4 Walther Oncology Center
5 Department of Molecular Biology and Biochemistry
6 Department of Obstetrics and Gynecology
7 Richard L. Roudebush Veterans Affairs Medical Center, Indiana University School of Medicine, 535 Barnhill Drive, RT 473, Indianapolis, IN 46202, USA

* To whom correspondence should be addressed. Division of Hematology–Oncology, Department of Medicine, Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, 535 Barnhill Drive, RT 473, Indianapolis, IN 46202, USA. Tel: +1 317 278 8844; Fax: +1 317 278 0074; Email: dmatei{at}iupui.edu

Tissue transglutaminase (TG2), an enzyme involved in protein cross-linking and overexpressed in ovarian tumors, has antiapoptotic effects in cancer cells and may play a role in response to chemotherapy. In this study, we investigated the role of TG2 in the sensitivity of ovarian cancer cells to cisplatin. By using stable knockdown and overexpression strategies, we demonstrate that the level of expression of TG2 regulates apoptosis induced by cisplatin in SKOV3 and OV-90 ovarian cancer cells. Interestingly, not only TG2 knockdown but also a TG2 enzymatic inhibitor (KCC009) sensitized SKOV3 cells to cisplatin. To understand the mechanism by which TG2 exerts its antiapoptotic role, we examined the effects of protein kinase B (Akt) and nuclear factor-kappa B (NF-{kappa}B), two survival pathways commonly involved in development of drug resistance. Overexpression of the constitutively active p65 subunit of NF-{kappa}B, but not constitutively active Akt, rescued cells with diminished TG2 expression from cisplatin-induced apoptosis. This implicates activation of NF-{kappa}B as the main cisplatin resistance mechanism downstream of TG2. Indeed, NF-{kappa}B activity is decreased and the level of the inhibitory subunit I{kappa}B{alpha} is increased in ovarian cancer cells engineered to express diminished levels of TG2 or treated with the enzymatic inhibitor, KCC009. Our data show that TG2 prevents apoptosis induced by cisplatin by activating the NF-{kappa}B survival pathway in ovarian cancer cells.

Abbreviations: AFC, 7-amino-4-trifluoromethyl coumarin; Akt, protein kinase B; AS-TG2, anti-sense tissue transglutaminase; CI, combination index; EOC, epithelial ovarian cancer; FAK, focal adhesion kinase; IC50, 50% inhibitory concentration; I{kappa}B{alpha}, inhibitor of kappa B {alpha}; MTT, methylthiazolyldiphenyl-tetrazolium bromide; NF-{kappa}B, nuclear factor-kappa B; TdT, terminal deoxynucleotidyl transferase; TG, transglutaminase; XIAP, X-linked inhibitor of apoptosis protein

Received February 1, 2008; revised May 27, 2008; accepted June 22, 2008.


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