| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Carcinogenesis |
Departments of Nutrition [M. B. H-P., H. S., M. B. Z., J. W.] and Pathology [M. F. M., B. J.], University of Tennessee, Knoxville, Tennessee 37996
Nonsteroidal anti-inflammatory drugs (NSAIDs) are antitumorigenic in humans as well as in animal models of intestinal neoplasia, such as the adenomatous polyposis coli Min/+ (ApcMin/+) mouse. NSAIDs inhibit cyclooxygenase (COX) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the primary mechanism by which NSAIDs exert their antitumorigenic effects. However, mounting evidence suggests the existence of COX-independent mechanisms. In the present study, we attempted to clarify this issue by treating ApcMin/+ mice bearing established tumors with NSAIDs (piroxicam and sulindac, 0.5 and 0.6 mg/mouse/day, respectively) for 6 days and concomitantly bypassing COX inhibition by treatment with the E prostaglandin (EP) receptor agonists 16,16-dimethyl-prostaglandin E2 (PGE2) and 17-phenyl-trinor-PGE2 (10 µg each, three times daily) administered via gavage and/or i.p. routes. Treatment with piroxicam and sulindac resulted in 95% and 52% fewer tumors, respectively, and a higher ratio of apoptosis:mitosis in tumors from sulindac-treated mice as compared with controls. These effects were attenuated by concomitant EP receptor agonist treatment, suggesting PGE2 is important in the maintenance of tumor integrity. Immunological sequestration of PGE2 with an anti-PGE2 monoclonal antibody likewise resulted in 33% fewer tumors in ApcMin/+ mice relative to untreated controls, additionally substantiating a role for PGE2 in tumorigenesis. The EP receptor subtype EP1 mediates the effects of PGE2 by increasing intracellular calcium levels ([Ca2+]i), whereas antagonism of EP1 has been shown to attenuate tumorigenesis in ApcMin/+ mice. We demonstrate that [Ca2+]i is significantly elevated in tumors of ApcMin/+ mice relative to the adjacent normal-appearing mucosa. Furthermore, treatment with piroxicam results in significantly lower [Ca2+]i in tumors, and this effect is attenuated by concomitant treatment with the EP1/EP3 receptor agonist 17-phenyl-trinor-PGE2. Overall, our results suggest that NSAIDs exert their antitumorigenic effects, in part, via interference with PGE2 biosynthesis, and these effects may be mediated through changes in intracellular calcium levels.
This article has been cited by other articles:
|
|
 |
|
  M. A Frias, S. Somers, C. Gerber-Wicht, L. H Opie, S. Lecour, and U. Lang The PGE2-Stat3 interaction in doxorubicin-induced myocardial apoptosis Cardiovasc Res, July 9, 2008; (2008) cvn171v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. McEntee, C. Ziegler, D. Reel, K. Tomer, A. Shoieb, M. Ray, X. Li, N. Neilsen, F. B. Lih, D. O'Rourke, et al. Dietary n-3 Polyunsaturated Fatty Acids Enhance Hormone Ablation Therapy in Androgen-Dependent Prostate Cancer Am. J. Pathol., July 1, 2008; 173(1): 229 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Di Mari, J. I. Saada, R. C. Mifflin, J. D. Valentich, and D. W. Powell HETEs enhance IL-1-mediated COX-2 expression via augmentation of message stability in human colonic myofibroblasts Am J Physiol Gastrointest Liver Physiol, October 1, 2007; 293(4): G719 - G728. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Castellone, H. Teramoto, and J. S. Gutkind Cyclooxygenase-2 and Colorectal Cancer Chemoprevention: The {beta}-Catenin Connection Cancer Res., December 1, 2006; 66(23): 11085 - 11088. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.-C. Chuang, H. S. Sun, T.-M. Chen, and S.-J. Tsai Prostaglandin E2 Induces Fibroblast Growth Factor 9 via EP3-Dependent Protein Kinase C{delta} and Elk-1 Signaling Mol. Cell. Biol., November 15, 2006; 26(22): 8281 - 8292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Cai, Y.-T. Gao, W.-H. Chow, X.-O. Shu, G. Yang, B.-T. Ji, W. Wen, N. Rothman, H.-L. Li, J. D. Morrow, et al. Prospective Study of Urinary Prostaglandin E2 Metabolite and Colorectal Cancer Risk J. Clin. Oncol., November 1, 2006; 24(31): 5010 - 5016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Carothers, A. E. Moran, N. L. Cho, M. Redston, and M. M. Bertagnolli Changes in Antitumor Response in C57BL/6J-Min/+ Mice during Long-term Administration of a Selective Cyclooxygenase-2 Inhibitor. Cancer Res., June 15, 2006; 66(12): 6432 - 6438. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D Wang and R N DuBois PROSTAGLANDINS AND CANCER Gut, January 1, 2006; 55(1): 115 - 122. [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Castellone, H. Teramoto, B. O. Williams, K. M. Druey, and J. S. Gutkind Prostaglandin E2 Promotes Colon Cancer Cell Growth Through a Gs-Axin-{beta}-Catenin Signaling Axis Science, December 2, 2005; 310(5753): 1504 - 1510. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Ulrich, J. Whitton, J.-H. Yu, J. Sibert, R. Sparks, J. D. Potter, and J. Bigler PTGS2 (COX-2) -765G > C Promoter Variant Reduces Risk of Colorectal Adenoma among Nonusers of Nonsteroidal Anti-inflammatory Drugs Cancer Epidemiol. Biomarkers Prev., March 1, 2005; 14(3): 616 - 619. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Whelan and M. F. McEntee Dietary (n-6) PUFA and Intestinal Tumorigenesis J. Nutr., December 1, 2004; 134(12): 3421S - 3426S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Simmons, R. M. Botting, and T. Hla Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition Pharmacol. Rev., September 1, 2004; 56(3): 387 - 437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Hull, S. C.W. Ko, and G. Hawcroft Prostaglandin EP receptors: Targets for treatment and prevention of colorectal cancer? Mol. Cancer Ther., August 1, 2004; 3(8): 1031 - 1039. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Pozzi, X. Yan, I. Macias-Perez, S. Wei, A. N. Hata, R. M. Breyer, J. D. Morrow, and J. H. Capdevila Colon Carcinoma Cell Growth Is Associated with Prostaglandin E2/EP4 Receptor-evoked ERK Activation J. Biol. Chem., July 9, 2004; 279(28): 29797 - 29804. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Ulrich, J. Bigler, R. Sparks, J. Whitton, J. G. Sibert, E. L. Goode, Y. Yasui, and J. D. Potter Polymorphisms in PTGS1 (=COX-1) and Risk of Colorectal Polyps Cancer Epidemiol. Biomarkers Prev., May 1, 2004; 13(5): 889 - 893. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-L. Su, J.-Y. Shih, M.-L. Yen, Y.-M. Jeng, C.-C. Chang, C.-Y. Hsieh, L.-H. Wei, P.-C. Yang, and M.-L. Kuo Cyclooxygenase-2 Induces EP1- and HER-2/Neu-Dependent Vascular Endothelial Growth Factor-C Up-Regulation: A Novel Mechanism of Lymphangiogenesis in Lung Adenocarcinoma Cancer Res., January 15, 2004; 64(2): 554 - 564. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Ziegler, L. Rainwater, J. Whelan, and M. F. McEntee Dietary Resveratrol Does Not Affect Intestinal Tumorigenesis in ApcMin/+ Mice J. Nutr., January 1, 2004; 134(1): 5 - 10. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kawamori, N. Uchiya, T. Sugimura, and K. Wakabayashi Enhancement of colon carcinogenesis by prostaglandin E2 administration Carcinogenesis, May 1, 2003; 24(5): 985 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Yu, N. R. Murray, C. Weems, L. Chen, H. Guo, R. Ethridge, J. D. Ceci, B. M. Evers, E. A. Thompson, and A. P. Fields Role of Cyclooxygenase 2 in Protein Kinase C beta II-mediated Colon Carcinogenesis J. Biol. Chem., March 21, 2003; 278(13): 11167 - 11174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dong, K. Guda, P. R. Nambiar, A. Rezaie, G. S. Belinsky, G. Lambeau, C. Giardina, and D. W. Rosenberg Inverse association between phospholipase A2 and COX-2 expression during mouse colon tumorigenesis Carcinogenesis, February 1, 2003; 24(2): 307 - 315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kitamura, T. Kawamori, N. Uchiya, M. Itoh, T. Noda, M. Matsuura, T. Sugimura, and K. Wakabayashi Inhibitory effects of mofezolac, a cyclooxygenase-1 selective inhibitor, on intestinal carcinogenesis Carcinogenesis, September 1, 2002; 23(9): 1463 - 1466. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
