Carcinogenesis Advance Access published online on July 29, 2008
Carcinogenesis, doi:10.1093/carcin/bgn158
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Tissue Transglutaminase Protects Epithelial Ovarian Cancer Cells from Cisplatin Induced Apoptosis by Promoting Cell Survival Signaling
1 Indiana University Department of Medicine
2 Indiana University Department of Surgery
3 Indiana University Melvin and Bren Simon Cancer Center
4 Walther Oncology Center
5 Indiana University 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, Indianapolis, IN, 46202
Address correspondence to: Daniela Matei, MD, Indiana University School of Medicine, 535 Barnhill Drive, RT 473, Indianapolis, IN, 46202, Tel.: (317) 278 8844, Fax: (317) 278 0074, e-mail: dmatei{at}iupui.edu
Tissue transglutaminase (TG2), an enzyme involved in protein crosslinking and overexpressed in ovarian tumors, has anti-apoptotic 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 knock-down 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 anti-apoptotic role, we examined the effects of Akt and NF-
B, two survival pathways commonly involved in development of drug resistance. Overexpression of the constitutively active p65 subunit of NF-B, but not constitutively active Akt, rescued cells with diminished TG2 expression from cisplatin-induced apoptosis. This implicates activation of NF-B as the main cisplatin resistance mechanism downstream of TG2. Indeed NF-B activity is decreased and the level of the inhibitory subunit IB
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-B survival pathway in ovarian cancer cells.
Key Words: ovarian cancer • tissue transglutaminase • cisplatin • chemotherapy resistance • NF-B
Received February 1, 2008; revised May 27, 2008; accepted June 22, 2008.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Ponnusamy, M. Pang, P. K. Annamaraju, Z. Zhang, R. Gong, Y. E. Chin, and S. Zhuang Transglutaminase-1 protects renal epithelial cells from hydrogen peroxide-induced apoptosis through activation of STAT3 and AKT signaling pathways Am J Physiol Renal Physiol, November 1, 2009; 297(5): F1361 - F1370. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Telci, R. J. Collighan, H. Basaga, and M. Griffin Increased TG2 Expression Can Result in Induction of Transforming Growth Factor {beta}1, Causing Increased Synthesis and Deposition of Matrix Proteins, Which Can Be Regulated by Nitric Oxide J. Biol. Chem., October 23, 2009; 284(43): 29547 - 29558. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. CHHABRA, A. VERMA, and K. MEHTA Tissue Transglutaminase Promotes or Suppresses Tumors Depending on Cell Context Anticancer Res, June 1, 2009; 29(6): 1909 - 1919. [Abstract] [Full Text] [PDF]
|
|