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Departments of Medicine [R. N. D., J. S., J. D. M.], Surgery [H. S., J. S., R. D. B.] and Cell Biology [R. D. B., R. N. D.], and Molecular Toxicology Center [R. N. D.], Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, Tennessee 37232-2279
Previously, we have shown that forced expression of prostaglandin endoperoxide synthase-2 [also called cyclooxygenase (COX) 2] leads to inhibition of programmed cell death in intestinal epithelial cells. More recently, we have demonstrated that growth of human colonic cancer xenografts is inhibited by treatment with a highly selective COX-2 inhibitor in tumors that express COX-2 (HCA-7) but not in those that lack COX-2 expression (HCT-116). To explore the biochemical mechanisms involved in these effects, we have evaluated the role of COX-2-derived eicosanoid products on programmed cell death in human colon cancer cells. Here we report that PGE2 treatment of human colon cancer cells leads to increased clonogenicity of HCA-7, but not HCT-116 cells. Treatment with a highly selective COX-2 inhibitor (SC-58125) decreases colony formation in monolayer culture and this growth inhibition was reversed by treatment with PGE2. Additionally, PGE2 inhibits programmed cell death caused by SC-58125 and induces Bcl-2 expression, but did not affect Bcl-x or Bax expression in human colon cancer (HCA-7) cells. Therefore, decreased cell death caused by PGE2 would enhance the tumorigenic potential of intestinal epithelial cells. Thus, these results may help to explain a component of the mechanism by which COX inhibitors prevent colorectal cancer in humans.
1 This study was supported by USPHS Grants DK-47297 (to R. N. D.), GM-53319 (to R. D. B.), CA-69457 (to R. D. B.), DK-48831 (to J. D. M.), GM-15431, and GM-42056 (to J. D. M.); National Institute of Environmental Health Sciences Grant 00267; and the Veterans Affairs Merit Grant (to R. N. D.).
2 To whom requests for reprints should be addressed, at the Department of Medicine/GI, MCN C-2104, Vanderbilt University Medical Center, Nashville, TN 37232-2279. Phone: (615) 343-8989; Fax: (615) 343-6229; E-mail: duboism@ctrvax.vanderbilt.edu.
Received 7/22/97. Accepted 11/11/97.
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 K. Takenaka, E. Ogawa, H. Oyanagi, H. Wada, and F. Tanaka Carbonyl Reductase Expression and Its Clinical Significance in Non-Small-Cell Lung Cancer Cancer Epidemiol. Biomarkers Prev., August 1, 2005; 14(8): 1972 - 1975. [Abstract] [Full Text] [PDF]
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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]
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L A A Brosens, J J Keller, G J A Offerhaus, M Goggins, and F M Giardiello Prevention and management of duodenal polyps in familial adenomatous polyposis Gut, July 1, 2005; 54(7): 1034 - 1043. [Full Text] [PDF]
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Y. Denkins, D. Kempf, M. Ferniz, S. Nileshwar, and D. Marchetti Role of {omega}-3 polyunsaturated fatty acids on cyclooxygenase-2 metabolism in brain-metastatic melanoma J. Lipid Res., June 1, 2005; 46(6): 1278 - 1284. [Abstract] [Full Text] [PDF]
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 V. Mollace, C. Muscoli, E. Masini, S. Cuzzocrea, and D. Salvemini Modulation of Prostaglandin Biosynthesis by Nitric Oxide and Nitric Oxide Donors Pharmacol. Rev., June 1, 2005; 57(2): 217 - 252. [Abstract] [Full Text] [PDF]
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 N. Kawada, G. Solis, N. Ivey, S. Connors, K. Dennehy, P. Modlinger, R. Hamel, J. T. Kawada, E. Imai, R. Langenbach, et al. Cyclooxygenase-1-Deficient Mice Have High Sleep-to-Wake Blood Pressure Ratios and Renal Vasoconstriction Hypertension, June 1, 2005; 45(6): 1131 - 1138. [Abstract] [Full Text] [PDF]
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K. Uchida, S. Schneider, J. M. Yochim, H. Kuramochi, K. Hayashi, K. Takasaki, D. Yang, K. D. Danenberg, and P. V. Danenberg Intratumoral COX-2 Gene Expression Is a Predictive Factor for Colorectal Cancer Response to Fluoropyrimidine-Based Chemotherapy Clin. Cancer Res., May 1, 2005; 11(9): 3363 - 3368. [Abstract] [Full Text] [PDF]
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J. R. Brown and R. N. DuBois COX-2: A Molecular Target for Colorectal Cancer Prevention J. Clin. Oncol., April 20, 2005; 23(12): 2840 - 2855. [Abstract] [Full Text] [PDF]
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K. Oh, W. C. Willett, C. S. Fuchs, and E. Giovannucci Dietary Marine n-3 Fatty Acids in Relation to Risk of Distal Colorectal Adenoma in Women Cancer Epidemiol. Biomarkers Prev., April 1, 2005; 14(4): 835 - 841. [Abstract] [Full Text] [PDF]
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D. Wang, F. G. Buchanan, H. Wang, S. K. Dey, and R. N. DuBois Prostaglandin E2 Enhances Intestinal Adenoma Growth via Activation of the Ras-Mitogen-Activated Protein Kinase Cascade Cancer Res., March 1, 2005; 65(5): 1822 - 1829. [Abstract] [Full Text] [PDF]
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 S. K. Kolluri, M. Corr, S. Y. James, M. Bernasconi, D. Lu, W. Liu, H. B. Cottam, L. M. Leoni, D. A. Carson, and X.-k. Zhang The R-enantiomer of the nonsteroidal antiinflammatory drug etodolac binds retinoid X receptor and induces tumor-selective apoptosis PNAS, February 15, 2005; 102(7): 2525 - 2530. [Abstract] [Full Text] [PDF]
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M. G. Backlund, J. R. Mann, V. R. Holla, F. G. Buchanan, H.-H. Tai, E. S. Musiek, G. L. Milne, S. Katkuri, and R. N. DuBois 15-Hydroxyprostaglandin Dehydrogenase Is Down-regulated in Colorectal Cancer J. Biol. Chem., February 4, 2005; 280(5): 3217 - 3223. [Abstract] [Full Text] [PDF]
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C. K. Nielsen, J. I.A. Campbell, J. F. Ohd, M. Morgelin, K. Riesbeck, G. Landberg, and A. Sjolander A Novel Localization of the G-Protein-Coupled CysLT1 Receptor in the Nucleus of Colorectal Adenocarcinoma Cells Cancer Res., February 1, 2005; 65(3): 732 - 742. [Abstract] [Full Text] [PDF]
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 S.-H. Kim, Y.-H. Kim, K.-J. Shin, Y.-S. Oh, C. S. Lee, K.-O. Kang, S. H. Ryu, and P.-G. Suh 2,2',4,6,6'-Pentachlorobiphenyl-Induced Apoptosis Is Limited by Cyclooxygenase-2 Induction Toxicol. Sci., February 1, 2005; 83(2): 397 - 404. [Abstract] [Full Text] [PDF]
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A. J. Dannenberg, S. M. Lippman, J. R. Mann, K. Subbaramaiah, and R. N. DuBois Cyclooxygenase-2 and Epidermal Growth Factor Receptor: Pharmacologic Targets for Chemoprevention J. Clin. Oncol., January 10, 2005; 23(2): 254 - 266. [Abstract] [Full Text] [PDF]
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V. R. Holla, D. Wang, J. R. Brown, J. R. Mann, S. Katkuri, and R. N. DuBois Prostaglandin E2 Regulates the Complement Inhibitor CD55/Decay-accelerating Factor in Colorectal Cancer J. Biol. Chem., January 7, 2005; 280(1): 476 - 483. [Abstract] [Full Text] [PDF]
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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]
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Y. Ding, M. Tong, S. Liu, J. A. Moscow, and H.-H. Tai NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer Carcinogenesis, January 1, 2005; 26(1): 65 - 72. [Abstract] [Full Text] [PDF]
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D. S. Dandekar and B. L. Lokeshwar Inhibition of Cyclooxygenase (COX)-2 Expression by Tet-Inducible COX-2 Antisense cDNA in Hormone-Refractory Prostate Cancer Significantly Slows Tumor Growth and Improves Efficacy of Chemotherapeutic Drugs Clin. Cancer Res., December 1, 2004; 10(23): 8037 - 8047. [Abstract] [Full Text] [PDF]
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B. Hinz, R. Ramer, K. Eichele, U. Weinzierl, and K. Brune Up-Regulation of Cyclooxygenase-2 Expression Is Involved in R(+)-Methanandamide-Induced Apoptotic Death of Human Neuroglioma Cells Mol. Pharmacol., December 1, 2004; 66(6): 1643 - 1651. [Abstract] [Full Text] [PDF]
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 G. D. Basu, L. B. Pathangey, T. L. Tinder, M. LaGioia, S. J. Gendler, and P. Mukherjee Cyclooxygenase-2 Inhibitor Induces Apoptosis in Breast Cancer Cells in an In vivo Model of Spontaneous Metastatic Breast Cancer Mol. Cancer Res., November 1, 2004; 2(11): 632 - 642. [Abstract] [Full Text] [PDF]
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W.-C. Huang, S.-T. Chan, T.-L. Yang, C.-C. Tzeng, and C.-C. Chen Inhibition of ICAM-1 gene expression, monocyte adhesion and cancer cell invasion by targeting IKK complex: molecular and functional study of novel {alpha}-methylene-{gamma}-butyrolactone derivatives Carcinogenesis, October 1, 2004; 25(10): 1925 - 1934. [Abstract] [Full Text] [PDF]
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K. Krysan, H. Dalwadi, S. Sharma, M. Pold, and S. Dubinett Cyclooxygenase 2-Dependent Expression of Survivin Is Critical for Apoptosis Resistance in Non-Small Cell Lung Cancer Cancer Res., September 15, 2004; 64(18): 6359 - 6362. [Abstract] [Full Text] [PDF]
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F. Khwaja, J. Allen, J. Lynch, P. Andrews, and D. Djakiew Ibuprofen Inhibits Survival of Bladder Cancer Cells by Induced Expression of the p75NTR Tumor Suppressor Protein Cancer Res., September 1, 2004; 64(17): 6207 - 6213. [Abstract] [Full Text] [PDF]
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A. F. Badawi, Y. Liu, M. B. Eldeen, W. Morrow, Z. R. Razak, M. Maradeo, and M. Z. Badr Age-associated changes in the expression pattern of cyclooxygenase-2 and related apoptotic markers in the cancer susceptible region of rat prostate Carcinogenesis, September 1, 2004; 25(9): 1681 - 1688. [Abstract] [Full Text] [PDF]
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P. A. Adegboyega, O. Ololade, J. Saada, R. Mifflin, J. F. Di Mari, and D. W. Powell Subepithelial Myofibroblasts Express Cyclooxygenase-2 in Colorectal Tubular Adenomas Clin. Cancer Res., September 1, 2004; 10(17): 5870 - 5879. [Abstract] [Full Text] [PDF]
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M. Schenning, C. M. van Tiel, D. van Manen, J. C. Stam, B. M. Gadella, K. W. A. Wirtz, and G. T. Snoek Phosphatidylinositol transfer protein {alpha} regulates growth and apoptosis of NIH3T3 cells: involvement of a cannabinoid 1-like receptor J. Lipid Res., August 1, 2004; 45(8): 1555 - 1564. [Abstract] [Full Text] [PDF]
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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]
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J. Biarc, I. S. Nguyen, A. Pini, F. Gosse, S. Richert, D. Thierse, A. Van Dorsselaer, E. Leize-Wagner, F. Raul, J.-P. Klein, et al. Carcinogenic properties of proteins with pro-inflammatory activity from Streptococcus infantarius (formerly S.bovis) Carcinogenesis, August 1, 2004; 25(8): 1477 - 1484. [Abstract] [Full Text] [PDF]
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J. C. H. Hardwick, M. van Santen, G. R. van den Brink, S. J. H. van Deventer, and M. P. Peppelenbosch DNA array analysis of the effects of aspirin on colon cancer cells: involvement of Rac1 Carcinogenesis, July 1, 2004; 25(7): 1293 - 1298. [Abstract] [Full Text] [PDF]
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C. T. Dang, A. J. Dannenberg, K. Subbaramaiah, M. N. Dickler, M. M. Moasser, A. D. Seidman, G. M. D'Andrea, M. Theodoulou, K. S. Panageas, L. Norton, et al. Phase II Study of Celecoxib and Trastuzumab in Metastatic Breast Cancer Patients Who Have Progressed after Prior Trastuzumab-Based Treatments Clin. Cancer Res., June 15, 2004; 10(12): 4062 - 4067. [Abstract] [Full Text] [PDF]
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 V. Quidville, N. Segond, E. Pidoux, R. Cohen, A. Jullienne, and S. Lausson Tumor Growth Inhibition by Indomethacin in a Mouse Model of Human Medullary Thyroid Cancer: Implication of Cyclooxygenases and 15-Hydroxyprostaglandin Dehydrogenase Endocrinology, May 1, 2004; 145(5): 2561 - 2571. [Abstract] [Full Text] [PDF]
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T. Almahmeed, J. O. Boyle, E. G. Cohen, J. F. Carew, B. Du, N. K. Altorki, L. Kopelovich, J.-L. Fang, P. Lazarus, K. Subbaramaiah, et al. Benzo[a]pyrene phenols are more potent inducers of CYP1A1, CYP1B1 and COX-2 than benzo[a]pyrene glucuronides in cell lines derived from the human aerodigestive tract Carcinogenesis, May 1, 2004; 25(5): 793 - 799. [Full Text] [PDF]
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J. Shao, B. M. Evers, and H. Sheng Prostaglandin E2 Synergistically Enhances Receptor Tyrosine Kinase-dependent Signaling System in Colon Cancer Cells J. Biol. Chem., April 2, 2004; 279(14): 14287 - 14293. [Abstract] [Full Text] [PDF]
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