| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Tumor Biology |
Departments of Gastrointestinal Medicine and Nutrition [Y. S., X. M. T., E. H., F. A. S.], and Molecular Pathology [M. T. K.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
The cyclooxygenase-2 (COX-2) gene encodes an inducible enzyme that converts arachidonic acid to prostaglandins and is up-regulated in colorectal neoplasms. Evidence indicates that COX-2 may regulate apoptosis and can influence the malignant phenotype. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX enzymes and induce apoptosis in colorectal cancer cell lines, which may contribute to their antitumor effects. To determine whether forced COX-2 expression modulates susceptibility to drug-induced apoptosis, HCT-15 colon carcinoma cells were stably transfected with the COX-2 cDNA, and two clones overexpressing COX-2 were isolated. Selective COX-2 (NS398) and nonselective (sulindac sulfide) COX inhibitors, as well as 5-fluorouracil (5-FU), induced apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling in a dosage-dependent manner. Forced COX-2 expression significantly attenuated induction of apoptosis by all three of the drugs compared with parental HCT-15 cells. NSAIDs and 5-FU induced the mitochondrial release of cytochrome c as well as caspase-3 and -9 activation, and to a much lesser extent, caspase-8. COX-2-overexpressing cells showed reduced cytochrome c and caspase activation, relative to parental cells. A specific inhibitor of caspase-3 restored cell survival after drug treatment. COX-2 transfectants were found to overexpress the antiapoptotic Bcl-2 mRNA and protein relative to parental cells. In conclusion, forced COX-2 expression significantly attenuates apoptosis induction by NSAIDs and 5-FU through predominant inhibition of the cytochrome c-dependent apoptotic pathway. COX-2-mediated up-regulation of Bcl-2 suggests a potential mechanism for reduced apoptotic susceptibility.
This article has been cited by other articles:
|
|
 |
|
  Y. Sun, J. Chen, and B. Rigas Chemopreventive agents induce oxidative stress in cancer cells leading to COX-2 overexpression and COX-2-independent cell death Carcinogenesis, January 1, 2009; 30(1): 93 - 100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Adachi, Y. Tajima, T. Kuroki, T. Mishima, A. Kitasato, N. Tsuneoka, and T. Kanematsu Chemopreventive effects of a selective cyclooxygenase-2 inhibitor (etodolac) on chemically induced intraductal papillary carcinoma of the pancreas in hamsters Carcinogenesis, April 1, 2008; 29(4): 830 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Feng, J. R. Neale, M. A. Doll, and D. W. Hein Chemoprevention of Arylamine-Induced Colorectal Aberrant Crypts Experimental Biology and Medicine, January 1, 2008; 233(1): 71 - 75. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Iwase, T. Higuchi, T. Gonda, H. Kobayashi, H. Uetake, M. Enomoto, and K. Sugihara The Effect of Meloxicam, a Selective COX-2 Inhibitor, on the Microvasculature of Small Metastatic Liver Tumors in Rats Jpn. J. Clin. Oncol., September 1, 2007; 37(9): 673 - 678. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-S. Chun, J. K. Akunda, and R. Langenbach Cyclooxygenase-2 Inhibits UVB-Induced Apoptosis in Mouse Skin by Activating the Prostaglandin E2 Receptors, EP2 and EP4 Cancer Res., March 1, 2007; 67(5): 2015 - 2021. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Cianchi, C. Cortesini, L. Magnelli, E. Fanti, L. Papucci, N. Schiavone, L. Messerini, A. Vannacci, S. Capaccioli, F. Perna, et al. Inhibition of 5-lipoxygenase by MK886 augments the antitumor activity of celecoxib in human colon cancer cells. Mol. Cancer Ther., November 1, 2006; 5(11): 2716 - 2726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Xu, S. Choudhary, O. Voznesensky, M. Mehrotra, M. Woodard, M. Hansen, H. Herschman, and C. Pilbeam Overexpression of Cox-2 in Human Osteosarcoma Cells Decreases Proliferation and Increases Apoptosis. Cancer Res., July 1, 2006; 66(13): 6657 - 6664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zhi, L. Wang, J. Zhang, C. Zhou, F. Ding, A. Luo, M. Wu, Q. Zhan, and Z. Liu Significance of COX-2 expression in human esophageal squamous cell carcinoma Carcinogenesis, June 1, 2006; 27(6): 1214 - 1221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Martin, D. C. Phillips, K. Szekely-Szucs, L. Elghazi, F. Desmots, and J. A. Houghton Cyclooxygenase-2 Inhibition Sensitizes Human Colon Carcinoma Cells to TRAIL-Induced Apoptosis through Clustering of DR5 and Concentrating Death-Inducing Signaling Complex Components into Ceramide-Enriched Caveolae Cancer Res., December 15, 2005; 65(24): 11447 - 11458. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. Sinicrope and R. C. Penington Sulindac sulfide-induced apoptosis is enhanced by a small-molecule Bcl-2 inhibitor and by TRAIL in human colon cancer cells overexpressing Bcl-2 Mol. Cancer Ther., October 1, 2005; 4(10): 1475 - 1483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Rigas and K. Kashfi Cancer Prevention: A New Era beyond Cyclooxygenase-2 J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 1 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Santini, B. Vincenzi, G. Tonini, S. Scarpa, F. Vasaturo, C. Malacrino, F. Vecchio, D. Borzomati, S. Valeri, R. Coppola, et al. Cyclooxygenase-2 Overexpression Is Associated with a Poor Outcome in Resected Ampullary Cancer Patients Clin. Cancer Res., May 15, 2005; 11(10): 3784 - 3789. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. W. Yim, H.-S. Jong, T. Y. Kim, H. H. Choi, S. G. Kim, S. H. Song, J. Kim, S.-G. Ko, J. W. Lee, T.-Y. Kim, et al. Cyclooxygenase-2 Inhibits Novel Ginseng Metabolite-Mediated Apoptosis Cancer Res., March 1, 2005; 65(5): 1952 - 1960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Tsuneoka, Y. Tajima, A. Kitazato, K. Fukuda, T. Kitajima, T. Kuroki, S. Onizuka, and T. Kanematsu Chemopreventative effect of a cyclooxygenase-2-specific inhibitor (etodolac) on chemically induced biliary carcinogenesis in hamsters Carcinogenesis, February 1, 2005; 26(2): 465 - 469. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sun and F. A. Sinicrope Selective inhibitors of MEK1/ERK44/42 and p38 mitogen-activated protein kinases potentiate apoptosis induction by sulindac sulfide in human colon carcinoma cells Mol. Cancer Ther., January 1, 2005; 4(1): 51 - 59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Jiang, J. Wong, H. Fyrst, J. D. Saba, and B. N. Ames {gamma}-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis PNAS, December 21, 2004; 101(51): 17825 - 17830. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Jang, H. J. Kang, J. R. Kim, and C. H. Yang Non-steroidal anti-inflammatory drug activated gene (NAG-1) expression is closely related to death receptor-4 and -5 induction, which may explain sulindac sulfide induced gastric cancer cell apoptosis Carcinogenesis, October 1, 2004; 25(10): 1853 - 1858. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Ishimura, S. F. Bronk, and G. J. Gores Inducible nitric oxide synthase upregulates cyclooxygenase-2 in mouse cholangiocytes promoting cell growth Am J Physiol Gastrointest Liver Physiol, July 1, 2004; 287(1): G88 - G95. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Sinicrope, E. Half, J. S. Morris, P. M. Lynch, J. D. Morrow, B. Levin, E. T. Hawk, D. S. Cohen, G. D. Ayers, and L. C. Stephens Cell Proliferation and Apoptotic Indices Predict Adenoma Regression in a Placebo-Controlled Trial of Celecoxib in Familial Adenomatous Polyposis Patients Cancer Epidemiol. Biomarkers Prev., June 1, 2004; 13(6): 920 - 927. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. de Pascual-Teresa, K. L. Johnston, M. S. DuPont, K. A. O'Leary, P. W. Needs, L. M. Morgan, M. N. Clifford, Y. Bao, and G. Williamson Quercetin Metabolites Downregulate Cyclooxygenase-2 Transcription in Human Lymphocytes Ex Vivo but Not In Vivo J. Nutr., March 1, 2004; 134(3): 552 - 557. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.-M. Simeone, Y.-J. Li, L. D. Broemeling, M. M. Johnson, M. Tuna, and A. M. Tari Cyclooxygenase-2 Is Essential for HER2/neu to Suppress N- (4-Hydroxyphenyl)retinamide Apoptotic Effects in Breast Cancer Cells Cancer Res., February 15, 2004; 64(4): 1224 - 1228. [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]
|
|
|
|
 |
|
 N. Hendrickx, C. Volanti, U. Moens, O. M. Seternes, P. de Witte, J. R. Vandenheede, J. Piette, and P. Agostinis Up-regulation of Cyclooxygenase-2 and Apoptosis Resistance by p38 MAPK in Hypericin-mediated Photodynamic Therapy of Human Cancer Cells J. Biol. Chem., December 26, 2003; 278(52): 52231 - 52239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Ardies Inflammation as Cause for Scar Cancers of the Lung Integr Cancer Ther, September 1, 2003; 2(3): 238 - 246. [Abstract] [PDF]
|
|
|
|
|
|
H. Nishihara, S. Kizaka-Kondoh, P. A. Insel, and L. Eckmann Inhibition of apoptosis in normal and transformed intestinal epithelial cells by cAMP through induction of inhibitor of apoptosis protein (IAP)-2 PNAS, July 22, 2003; 100(15): 8921 - 8926. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. G. Bottone Jr., J. M. Martinez, J. B. Collins, C. A. Afshari, and T. E. Eling Gene Modulation by the Cyclooxygenase Inhibitor, Sulindac Sulfide, in Human Colorectal Carcinoma Cells: POSSIBLE LINK TO APOPTOSIS J. Biol. Chem., July 3, 2003; 278(28): 25790 - 25801. [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 |
