QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.091363v1 316/1/25    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hundley, T. R. Articles by Rigas, B. Search for Related Content PubMed PubMed Citation Articles by Hundley, T. R. Articles by Rigas, B.

CELLULAR AND MOLECULAR

Nitric Oxide-Donating Aspirin Inhibits Colon Cancer Cell Growth via Mitogen-Activated Protein Kinase Activation

Division of Cancer Prevention, Department of Medicine, State University of New York, Stony Brook, New York

Nitric oxide-donating aspirin (NO-aspirin), representing a new concept in the development of more efficacious nonsteroidal anti-inflammatory drugs, consists of traditional aspirin bearing -ONO₂, which releases NO. Conventional aspirin prevents human colon cancer, but its toxicity precludes its application as a chemopreventive agent. NO-aspirin seems safer and in cultured cancer cells it is >1000-fold more potent than aspirin. To determine the mechanism by which NO-aspirin inhibits cell growth, we studied its effect on mitogen-activated protein kinase (MAPK) signaling in HT-29 human colon cancer cells. NO-aspirin stimulated the phosphorylation of extracellular signal-regulated kinase 1/2 and Akt only marginally. The greatest increases in phosphorylation were seen in cJun NH₂-terminal kinase (JNK) and p38 MAP kinases, which were observed as early as 5 min and after 1 h of treatment, averaged more than 10-fold over control. The activation of JNK and p38 was accompanied by large increases in the phosphorylation of the downstream transcription factors cJun and activating transcription factor 2 (ATF-2). We used specific MAPK inhibitors, small interfering (siRNA) gene silencing methods, and dominant-negative cJun to determine the relevance of these phosphorylation events to the ability of NO-aspirin to inhibit colon cancer cell growth. Only the dual inhibitor of p38 and JNK and the use of combined siRNA silencing of p38 and cJun abrogated the ability of NO-aspirin to block cell growth. Our data indicate that NO-aspirin is dependent on both the p38 and the JNK MAP kinase pathways for its ability to inhibit the growth of colon cancer cells.

Address correspondence to: Dr. Basil Rigas, Division of Cancer Prevention, Department of Medicine, Life Sciences Bldg. 06, SUNY at Stony Brook, Stony Brook, NY 11794-5200. E-mail: basil.rigas{at}sunysb.edu

This article has been cited by other articles:

				D. Maksimovic-Ivanic, S. Mijatovic, L. Harhaji, D. Miljkovic, D. Dabideen, K. Fan Cheng, K. Mangano, G. Malaponte, Y. Al-Abed, M. Libra, et al. Anticancer properties of the novel nitric oxide-donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide in vitro and in vivo Mol. Cancer Ther., March 1, 2008; 7(3): 510 - 520. [Abstract] [Full Text] [PDF]

				S. V. Singh, S. Choi, Y. Zeng, E.-R. Hahm, and D. Xiao Guggulsterone-Induced Apoptosis in Human Prostate Cancer Cells Is Caused by Reactive Oxygen Intermediate Dependent Activation of c-Jun NH2-Terminal Kinase Cancer Res., August 1, 2007; 67(15): 7439 - 7449. [Abstract] [Full Text] [PDF]

				C. V. Rao, B. S. Reddy, V. E. Steele, C-X Wang, X. Liu, N. Ouyang, J. M.R. Patlolla, B. Simi, L. Kopelovich, and B. Rigas Nitric oxide-releasing aspirin and indomethacin are potent inhibitors against colon cancer in azoxymethane-treated rats: effects on molecular targets. Mol. Cancer Ther., June 1, 2006; 5(6): 1530 - 1538. [Abstract] [Full Text] [PDF]

				J. Antosiewicz, A. Herman-Antosiewicz, S. W. Marynowski, and S. V. Singh c-Jun NH2-Terminal Kinase Signaling Axis Regulates Diallyl Trisulfide-Induced Generation of Reactive Oxygen Species and Cell Cycle Arrest in Human Prostate Cancer Cells. Cancer Res., May 15, 2006; 66(10): 5379 - 5386. [Abstract] [Full Text] [PDF]

				N. Ouyang, J. L. Williams, G. J. Tsioulias, J. Gao, M. J. Iatropoulos, L. Kopelovich, K. Kashfi, and B. Rigas Nitric oxide-donating aspirin prevents pancreatic cancer in a hamster tumor model. Cancer Res., April 15, 2006; 66(8): 4503 - 4511. [Abstract] [Full Text] [PDF]

				J. J. Turchi Nitric oxide and cisplatin resistance: NO easy answers PNAS, March 21, 2006; 103(12): 4337 - 4338. [Full Text] [PDF]