Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
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Signal Transduction Network Leading to COX-2 Induction: A Road Map in Search of Cancer Chemopreventives

  • Surh Young-Joon (National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University) ;
  • Kundu Joydeb Kumar (National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University)
  • Published : 2005.01.01
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Abstract

Cancer is still a major global health concern even after an everlasting strive in conquering this dread disease. Emphasis is now given to chemoprevention to reduce the risk of cancer and also to improve the quality of life among cancer afflicted individuals. Recent progress in molecular biology of cancer has identified key components of the cellular signaling network, whose functional abnormality results in undesired alterations in cellular homeostasis, creating a cellular microenvironment that favors premalignant and malignant transformation. Multiple lines of evidence suggest an elevated expression of cyclooxygenase-2 (COX-2) is causally linked to cancer. In response to oxidative/pro-inflammatory stimuli, turning on unusual signaling arrays mediated through diverse classes of kinases and transcription factors results in aberrant expression of COX-2. Population-based as well as laboratory studies have explored a broad spectrum of chemopreventive agents including selective COX-2 inhibitors and a wide variety of anti-inflammatory phytochemicals, which have been shown to target cellular signaling molecules as underlying mechanisms of chemoprevention. Thus, unraveling signaling pathways regulating aberrant COX-2 expression and targeted blocking of one or more components of those signal cascades may be exploited in searching chemopreventive agents in the future.

Keywords

References

  1. Aggarwal, B. B., Bhardwaj, A., Aggarwal, R. S., Seeram, N. P., Shishodia, S., and Takada, Y., Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res., 24, 2783-2840 (2004a)
  2. Aggarwal, S., Takada, Y., Singh, S., Myers, J. N., and Aggarwal, B. B., Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor-${\kappa}$B signaling. Int. J. Cancer, 111, 679-692 (2004b) https://doi.org/10.1002/ijc.20333
  3. Akarasereenont, P., Mitchell, J. A., Appleton, I., Thiemermann, C., and Vane, J. R., Involvement of tyrosine kinase in the induction of cyclo-oxygenase and nitric oxide synthase by endotoxin in cultured cells. Br. J. Pharmacol., 113, 1522- 1528 (1994) https://doi.org/10.1111/j.1476-5381.1994.tb17169.x
  4. Akarasereenont, P. and Thiemermann, C., The induction of cyclo-oxygenase-2 in human pulmonary epithelial cell culture (A549) activated by IL-1${\beta}$ is inhibited by tyrosine kinase inhibitors. Biochem. Biophys. Res. Commun., 220, 181-185 (1996) https://doi.org/10.1006/bbrc.1996.0377
  5. Allport, V. C., Slater, D. M., Newton, R., and Bennett, P. R., NF- ${\kappa}B$ and AP-1 are required for cyclo-oxygenase 2 gene expression in amnion epithelial cell line (WISH). Mol. Hum. Reprod., 6, 561-565 (2000) https://doi.org/10.1093/molehr/6.6.561
  6. Alshafie, G. A., Abou-Issa, H. M., Seibert, K., and Harris, R. E., Chemotherapeutic evaluation of Celecoxib, a cyclooxygenase- 2 inhibitor, in a rat mammary tumor model. Oncol. Rep., 7, 1377-1381 (2000)
  7. Aziz, M., Afaq, F., and Ahmad, N., Prevention of ultraviolet B radiation-damage by resveratrol in mouse skin is mediated via modulation in Survivin. Photochem. Photobiol., in press (2004)
  8. Baldwin, A. S., Jr., The NF-${\kappa}$B and I${\kappa}$B proteins: new discoveries and insights. Annu. Rev. Immunol., 14, 649-683 (1996) https://doi.org/10.1146/annurev.immunol.14.1.649
  9. Balkwill, F. and Mantovani, A., Inflammation and cancer: back to Virchow? Lancet, 357, 539-545 (2001) https://doi.org/10.1016/S0140-6736(00)04046-0
  10. Banerjee, S., Bueso-Ramos, C., and Aggarwal, B. B., Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factorkappaB, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res., 62, 4945-4954 (2002)
  11. Bennett, A., The production of prostanoids in human cancers, and their implications for tumor progression. Prog. Lipid Res., 25, 539-542 (1986) https://doi.org/10.1016/0163-7827(86)90109-8
  12. Bird, A. P. and Wolffe, A. P., Methylation-induced repression-- belts, braces, and chromatin. Cell, 99, 451-454 (1999) https://doi.org/10.1016/S0092-8674(00)81532-9
  13. Bird, T. A., Schooley, K., Dower, S. K., Hagen, H., and Virca, G. D., Activation of nuclear transcription factor NF-${\kappa}$B by interleukin-1 is accompanied by casein kinase II-mediated phosphorylation of the p65 subunit. J. Biol. Chem., 272, 32606-32612 (1997) https://doi.org/10.1074/jbc.272.51.32606
  14. Bode, A. M., Ma, W. Y., Surh, Y.-J., and Dong, Z., Inhibition of epidermal growth factor-induced cell transformation and activator protein 1 activation by [6]-gingerol. Cancer Res., 61, 850-853 (2001)
  15. Bortuzzo, C., Hanif, R., Kashfi, K., Staiano-Coico, L., Shiff, S. J., and Rigas, B., The effect of leukotrienes B and selected HETEs on the proliferation of colon cancer cells. Biochim. Biophys. Acta, 1300, 240-246 (1996) https://doi.org/10.1016/0005-2760(96)00003-3
  16. Caivano, M. and Cohen, P., Role of mitogen-activated protein kinase cascades in mediating lipopolysaccharide-stimulated induction of cyclooxygenase-2 and IL-1${\beta}$ in RAW264 macrophages. J. Immunol., 164, 3018-3025 (2000)
  17. Callejas, N. A., Fernandez-Martinez, A., Castrillo, A., Bosca, L., and Martin-Sanz, P., Selective inhibitors of cyclooxygenase-2 delay the activation of nuclear factor${\kappa}$B and attenuate the expression of inflammatory genes in murine macrophages treated with lipopolysaccharide. Mol. Pharmacol., 63, 671- 677 (2003) https://doi.org/10.1124/mol.63.3.671
  18. Canty, T. G., Jr., Boyle, E. M., Jr., Farr, A., Morgan, E. N., Verrier, E. D., and Pohlman, T. H., Oxidative stress induces NF-${\kappa}$B nuclear translocation without degradation of I${\kappa}$B${\alpha}$. Circulation, 100, II361-364 (1999) https://doi.org/10.1161/01.CIR.100.4.361
  19. Chan, G., Boyle, J. O., Yang, E. K., Zhang, F., Sacks, P. G., Shah, J. P., Edelstein, D., Soslow, R. A., Koki, A. T., Woerner, B. M., Masferrer, J. L., and Dannenberg, A. J., Cyclooxygenase- 2 expression is up-regulated in squamous cell carcinoma of the head and neck. Cancer Res., 59, 991-994 (1999)
  20. Chang, M. S., Chen, B. C., Yu, M. T., Sheu, J. R., Chen, T. F., and Lin, C. H., Phorbol 12-myristate 13-acetate upregulates cyclooxygenase-2 expression in human pulmonary epithelial cells via Ras, Raf-1, EPK, and NF-${\kappa}$B, but nop p38 MAPK, pathways. Cell Signal., 17, 299-310 (2005) https://doi.org/10.1016/j.cellsig.2004.07.008
  21. Chen, C. C., Sun, Y. T., Chen, J. J., and Chiu, K. T., TNF-alphainduced cyclooxygenase-2 expression in human lung epithelial cells: involvement of the phospholipase C-${\gamma}$2, protein kinase C-${\alpha}$, tyrosine kinase, NF-${\kappa}$B-inducing kinase, and I${\kappa}$B kinase 1/2 pathway. J. Immunol., 165, 2719-2728 (2000)
  22. Chen, C. W., Lee, S. T., Wu, W. T., Fu, W. M., Ho, F. M., and Lin, W. W., Signal transduction for inhibition of inducible nitric oxide synthase and cyclooxygenase-2 induction by capsaicin and related analogs in macrophages. Br. J. Pharmacol., 140, 1077-1087 (2003) https://doi.org/10.1038/sj.bjp.0705533
  23. Chun, K.-S., Kang, J.-Y., Kim, O.-H., Kang, H., and Surh, Y.-J., Effects of yakuchinone A and yakuchinone B on the phorbol ester-induced expression of COX-2 and iNOS and activation of NF-${\kappa}$B in mouse skin. J. Environ. Pathol. Toxicol. Oncol., 21, 131-139 (2002a)
  24. Chun, K.-S., Keum, Y.-S., Han, S.-S., Song, Y.-S., Kim, S.-H., and Surh, Y.-J., Curcumin inhibits phorbol ester-induced expression of cyclooxygenase-2 in mouse skin through suppression of extracellular signal-regulated kinase activity and NF-${\kappa}$B activation. Carcinogenesis, 24, 1515-1524 (2003) https://doi.org/10.1093/carcin/bgg107
  25. Chun, K. S., Kim, S. H., Song, Y. S., and Surh, Y. J., Celecoxib inhibits phorbol ester-induced expression of COX-2 and activation of AP-1 and p38 MAP kinase in mouse skin. Carcinogenesis, 25, 713-722 (2004) https://doi.org/10.1093/carcin/bgh076
  26. Chun, K.-S., Park, K.-K., Lee, J., Kang, M., and Surh, Y.-J., Inhibition of mouse skin tumor promotion by antiinflammatory diarylheptanoids derived from Alpinia oxyphylla Miquel (Zingiberaceae). Oncol. Res., 13, 37-45 (2002b)
  27. Chun, K.-S. and Surh, Y.-J., Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention. Biochem. Pharmacol., 68, 1089-1100 (2004) https://doi.org/10.1016/j.bcp.2004.05.031
  28. Clevers, H., At the crossroads of inflammation and cancer. Cell, 118, 671-674 (2004) https://doi.org/10.1016/j.cell.2004.09.005
  29. Conney, A. H., Lou, Y. R., Xie, J. G., Osawa, T., Newmark, H. L., Liu, Y., Chang, R. L., and Huang, M. T., Some perspectives on dietary inhibition of carcinogenesis: studies with curcumin and tea. Proc. Soc. Exp. Biol. Med., 216, 234-245 (1997)
  30. Cui, Y., Kim, D. S., Park, S. H., Yoon, J. A., Kim, S. K., Kwon, S. B., and Park, K. C., Involvement of ERK and p38 MAP kinase in AAPH-induced COX-2 expression in HaCaT cells. Chem. Phys. Lipids, 129, 43-52 (2004) https://doi.org/10.1016/j.chemphyslip.2003.11.004
  31. D'Acquisto, F., Iuvone, T., Rombola, L., Sautebin, L., Di Rosa, M. and Carnuccio, R., Involvement of NF-${\kappa}$B in the regulation of cyclooxygenase-2 protein expression in LPS-stimulated J774 macrophages. FEBS Lett., 418, 175-178 (1997) https://doi.org/10.1016/S0014-5793(97)01377-X
  32. Dannenberg, A. J., Altorki, N. K., Boyle, J. O., Dang, C., Howe, L. R., Weksler, B. B., and Subbaramaiah, K., Cyclo-oxygenase 2: a pharmacological target for the prevention of cancer. Lancet Oncol., 2, 544-551 (2001) https://doi.org/10.1016/S1470-2045(01)00488-0
  33. Deak, M., Clifton, A. D., Lucocq, L. M., and Alessi, D. R., Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J., 17, 4426-4441 (1998) https://doi.org/10.1093/emboj/17.15.4426
  34. Duvoix, A., Delhalle, S., Blasius, R., Schnekenburger, M., Morceau, F., Fougere, M., Henry, E., Galteau, M. M., Dicato, M., and Diederich, M., Effect of chemopreventive agents on glutathione S-transferase P1-1 gene expression mechanisms via activating protein 1 and nuclear factor ${\kappa}$B inhibition. Biochem. Pharmacol., 68, 1101-1111 (2004) https://doi.org/10.1016/j.bcp.2004.05.032
  35. Evans, J. F., Rofecoxib (Vioxx), a specific cyclooxygenase-2 inhibitor, is chemopreventive in a mouse model of colon cancer. Am. J. Clin. Oncol., 26, S62-65 (2003)
  36. Fischer, S. M., Lo, H. H., Gordon, G. B., Seibert, K., Kelloff, G., Lubet, R. A., and Conti, C. J., Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis. Mol. Carcinog., 25, 231-240 (1999) https://doi.org/10.1002/(SICI)1098-2744(199908)25:4<231::AID-MC1>3.0.CO;2-F
  37. Gerritsen, M. E., Williams, A. J., Neish, A. S., Moore, S., Shi, Y., and Collins, T., CREB-binding protein/p300 are transcriptional coactivators of p65. Proc. Natl. Acad. Sci. U.S.A., 94, 2927- 2932 (1997) https://doi.org/10.1073/pnas.94.7.2927
  38. Ghosh, S. and Karin, M., Missing pieces in the NF-${\kappa}$B puzzle. Cell, 109, S81-S96 (2002) https://doi.org/10.1016/S0092-8674(02)00703-1
  39. Giardiello, F. M., Offerhaus, G. J., and DuBois, R. N., The role of nonsteroidal anti-inflammatory drugs in colorectal cancer prevention. Eur. J. Cancer, 31A, 1071-1076 (1995) https://doi.org/10.1016/0959-8049(95)00137-8
  40. Giovannucci, E., Egan, K. M., Hunter, D. J., Stampfer, M. J., Colditz, G. A., Willett, W. C., and Speizer, F. E., Aspirin and the risk of colorectal cancer in women. N. Engl. J. Med., 333, 609-614 (1995) https://doi.org/10.1056/NEJM199509073331001
  41. Gorgoni, B., Caivano, M., Arizmendi, C., and Poli, V., The transcription factor C/EBP${\beta}$ is essential for inducible expression of the cox-2 gene in macrophages but not in fibroblasts. J. Biol. Chem., 276, 40769-40777 (2001) https://doi.org/10.1074/jbc.M106865200
  42. Greenberg, E. R., Baron, J. A., Freeman, D. H., Jr., Mandel, J. S., and Haile, R., Reduced risk of large-bowel adenomas among aspirin users. The Polyp Prevention Study Group. J. Natl. Cancer Inst., 85, 912-916 (1993) https://doi.org/10.1093/jnci/85.11.912
  43. Greten, F. R., Eckmann, L., Greten, T. F., Park, J. M., Li, Z. W., Egan, L. J., Kagnoff, M. F., and Karin, M., IKK${\beta}$ links inflammation and tumorigenesis in a mouse model of colitisassociated cancer. Cell, 118, 285-296 (2004) https://doi.org/10.1016/j.cell.2004.07.013
  44. Grubbs, C. J., Lubet, R. A., Koki, A. T., Leahy, K. M., Masferrer, J. L., Steele, V. E., Kelloff, G. J., Hill, D. L., and Seibert, K., Celecoxib inhibits N-butyl-N-(4-hydroxybutyl)-nitrosamineinduced urinary bladder cancers in male B6D2F1 mice and female Fischer-344 rats. Cancer Res., 60, 5599-5602 (2000)
  45. Guan, Z., Buckman, S. Y., Miller, B. W., Springer, L. D., and Morrison, A. R., Interleukin-1$\beta$-induced cyclooxygenase-2 expression requires activation of both c-Jun $NH_2$-terminal kinase and p38 MAPK signal pathways in rat renal mesangial cells. J. Biol. Chem., 273, 28670-28676 (1998) https://doi.org/10.1074/jbc.273.44.28670
  46. Han, S.-S., Keum, Y.-S., Seo, H.-J., Chun, K.-S., Lee, S.-S., and Surh, Y.-J., Capsaicin suppresses phorbol ester-induced activation of NF-${\kappa}$B/Rel and AP-1 transcription factors in mouse epidermis. Cancer Lett., 164, 119-126 (2001) https://doi.org/10.1016/S0304-3835(01)00378-0
  47. Harnish, D. C., Scicchitano, M. S., Adelman, S. J., Lyttle, C. R., and Karathanasis, S. K., The role of CBP in estrogen receptor cross-talk with nuclear factor-${\kappa}$B in HepG2 cells. Endocrinology, 141, 3403-3411 (2000) https://doi.org/10.1210/en.141.9.3403
  48. Harris, R. E., Alshafie, G. A., Abou-Issa, H., and Seibert, K., Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Cancer Res., 60, 2101-2103 (2000)
  49. Huang, M. T., Newmark, H. L., and Frenkel, K., Inhibitory effects of curcumin on tumorigenesis in mice. J. Cell Biochem. Suppl., 27, 26-34 (1997) https://doi.org/10.1002/(SICI)1097-4644(1997)27+<26::AID-JCB7>3.0.CO;2-3
  50. Huang, W. C., Chen, J. J., Inoue, H., and Chen, C. C., Tyrosine phosphorylation of I${\kappa}$B kinase ${\alpha}$/${\beta}$ by protein kinase Cdependent c-Src activation is involved in TNF-${\alpha}$-induced cyclooxygenase-2 expression. J. Immunol., 170, 4767-4775 (2003)
  51. Hussain, T., Gupta, S., Adhami, V. M., and Mukhtar, H., Green tea constituent epigallocatechin-3-gallate selectively inhibits COX-2 without affecting COX-1 expression in human prostate carcinoma cells. Int. J. Cancer, 113, 660-669 (2005) https://doi.org/10.1002/ijc.20629
  52. Imbert, V., Rupec, R. A., Livolsi, A., Pahl, H. L., Traenckner, E. B., Mueller-Dieckmann, C., Farahifar, D., Rossi, B., Auberger, P., Baeuerle, P. A., and Peyron, J. F., Tyrosine phosphorylation of I${\kappa}$B-${\alpha}$ activates NF-${\kappa}$B without proteolytic degradation of I${\kappa}$B-${\alpha}$. Cell, 86, 787-798 (1996) https://doi.org/10.1016/S0092-8674(00)80153-1
  53. Inoue, H., Yokoyama, C., Hara, S., Tone, Y., and Tanabe, T., Transcriptional regulation of human prostaglandin-endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in vascular endothelial cells. Involvement of both nuclear factor for interleukin-6 expression site and cAMP response element. J. Biol. Chem., 270, 24965-24971 (1995) https://doi.org/10.1074/jbc.270.42.24965
  54. Itzkowitz, S. H. and Yio, X., Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am. J. Physiol. Gastrointest. Liver Physiol., 287, G7-17 (2004) https://doi.org/10.1152/ajpgi.00079.2004
  55. Jang, M., Cai, L., Udeani, G. O., Slowing, K. V., Thomas, C. F., Beecher, C. W., Fong, H. H., Farnsworth, N. R., Kinghorn, A. D., Mehta, R. G., Moon, R. C., and Pezzuto, J. M., Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science, 275, 218-220 (1997) https://doi.org/10.1126/science.275.5297.218
  56. Kang, G., Kong, P. J., Yuh, Y. J., Lim, S. Y., Yim, S. V., Chun, W., and Kim, S. S., Curcumin suppresses lipopolysaccharideinduced cyclooxygenase-2 expression by inhibiting activator protein 1 and nuclear factor ${\kappa}$B bindings in BV2 microglial cells. J. Pharmacol. Sci., 94, 325-328 (2004) https://doi.org/10.1254/jphs.94.325
  57. Kawamori, T., Rao, C. V., Seibert, K., and Reddy, B. S., Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, against colon carcinogenesis. Cancer Res., 58, 409-412 (1998)
  58. Keum, Y.-S., Han, S.-S., Chun, K.-S., Park, K.-K., Park, J.-H., Lee, S.-K., and Surh, Y.-J., Inhibitory effects of the ginsenoside $Rg_3$ on phorbol ester-induced cyclooxygenase- 2 expression, NF-${\kappa}$B activation and tumor promotion. Mutat. Res., 523-524, 75-85 (2003) https://doi.org/10.1016/S0027-5107(02)00323-8
  59. Kikuchi, T., Itoh, F., Toyota, M., Suzuki, H., Yamamoto, H., Fujita, M., Hosokawa, M., and Imai, K., Aberrant methylation and histone deacetylation of cyclooxygenase 2 in gastric cancer. Int. J. Cancer, 97, 272-277 (2002) https://doi.org/10.1002/ijc.1612
  60. Kim, C. S., Kawada, T., Kim, B. S., Han, I. S., Choe, S. Y., Kurata, T., and Yu, R., Capsaicin exhibits anti-inflammatory property by inhibiting $I{\kappa}B{\alpha}$ degradation in LPS-stimulated peritoneal macrophages. Cell Signal., 15, 299-306 (2003) https://doi.org/10.1016/S0898-6568(02)00086-4
  61. Kim, S.O., Chun, K.-S., Kundu, J., and Surh, Y.-J., Inhibitory effects of [6]-gingerol on PMA-induced COX-2 expression and activation of NF-${\kappa}$B and p38 MAPK in mouse skin. Biofactors, 21, 27-31 (2004) https://doi.org/10.1002/biof.552210107
  62. Kim, S. O., Kundu, J. K., Shin, Y., Park, J.-H., Cho, M.-H., Kim, T.-Y., and Surh, Y.-J., [6]-Gingerol inhibits COX-2 expression by blocking the activation of p38 MAP kinase and NF-${\kappa}$B in phorbol ester-stimulated mouse skin. Oncogene, in press (2005) https://doi.org/10.1038/sj.onc.1208446
  63. Kojima, M., Morisaki, T., Izuhara, K., Uchiyama, A., Matsunari, Y., Katano, M., and Tanaka, M., Lipopolysaccharide increases cyclo-oxygenase-2 expression in a colon carcinoma cell line through nuclear factor-${\kappa}$B activation. Oncogene, 19, 1225- 1231 (2000) https://doi.org/10.1038/sj.onc.1203427
  64. Koong, A. C., Chen, E. Y., Mivechi, N. F., Denko, N. C., Stambrook, P., and Giaccia, A. J., Hypoxic activation of nuclear factor-${\kappa}$B is mediated by a Ras and Raf signaling pathway and does not involve MAP kinase (ERK1 or ERK2). Cancer Res., 54, 5273-5279 (1994)
  65. Kosaka, T., Miyata, A., Ihara, H., Hara, S., Sugimoto, T., Takeda, O., Takahashi, E., and Tanabe, T., Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2. Eur. J. Biochem., 221, 889-897 (1994) https://doi.org/10.1111/j.1432-1033.1994.tb18804.x
  66. Kundu, J. K., Chun, K.-S., Kim, S. O., and Surh, Y.-J., Resveratrol inhibits phorbol ester-induced cyclooxygenase-2 expression in mouse skin: MAPKs and AP-1 as potential molecular targets. Biofactors, 21, 33-39 (2004) https://doi.org/10.1002/biof.552210108
  67. Kundu, J. K., Na, H.-K., Chun, K.-S., Kim, Y.-K., Lee, S. J., Lee, S. S., Lee, O.-S., Sim, Y.-C., and Surh, Y.-J., Inhibition of phorbol ester-induced COX-2 expression by epigallocatechin gallate in mouse skin and cultured human mammary epithelial cells. J. Nutr., 133, 3805S-3810S (2003)
  68. Kundu, J. K. and Surh, Y.-J., Molecular basis of chemoprevention by resveratrol: NF-${\kappa}$B and AP-1 as potential targets. Mutat. Res., 555, 65-80 (2004) https://doi.org/10.1016/j.mrfmmm.2004.05.019
  69. Leahy, K. M., Ornberg, R. L., Wang, Y., Zweifel, B. S., Koki, A. T., and Masferrer, J. L., Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res., 62, 625-631 (2002)
  70. Lee, J.-Y., Shin, J.-W., Chun, K.-S., Park, K. K., Chung, W.-Y., Bang, Y.-J., Sung, J.-H., and Surh, Y.-J., Anti-tumor promotional effects of a novel intestinal bacterial metabolite (IH- 901) derived from the protopanaxadiol type ginsenosides in mouse skin. Carcinogenesis, in press
  71. Leung, W. K., To, K. F., Ng, Y. P., Lee, T. L., Lau, J. Y., Chan, F. K., Ng, E. K., Chung, S. C., and Sung, J. J., Association between cyclo-oxygenase-2 overexpression and missense p53 mutations in gastric cancer. Br. J. Cancer, 84, 335-339 (2001) https://doi.org/10.1054/bjoc.2000.1607
  72. Li, L., Aggarwal, B. B., Shishodia, S., Abbruzzese, J., and Kurzrock, R., Nuclear factor-${\kappa}$B and I${\kappa}$B kinase are constitutively active in human pancreatic cells, and their downregulation by curcumin (diferuloylmethane) is associated with the suppression of proliferation and the induction of apoptosis. Cancer, 101, 2351-2362 (2004) https://doi.org/10.1002/cncr.20605
  73. Li, Z. G., Shimada, Y., Sato, F., Maeda, M., Itami, A., Kaganoi, J., Komoto, I., Kawabe, A., and Imamura, M., Inhibitory effects of epigallocatechin-3-gallate on N-nitrosomethylbenzylamineinduced esophageal tumorigenesis in F344 rats. Int. J. Oncol., 21, 1275-1283 (2002)
  74. Liu, S. F., Ye, X., and Malik, A. B., Inhibition of NF-${\kappa}$B activation by pyrrolidine dithiocarbamate prevents in vivo expression of pro-inflammatory genes. Circulation, 100, 1330-1337 (1999) https://doi.org/10.1161/01.CIR.100.12.1330
  75. Liu, W., Reinmuth, N., Stoeltzing, O., Parikh, A. A., Tellez, C., Williams, S., Jung, Y. D., Fan, F., Takeda, A., Akagi, M., Bar- Eli, M., Gallick, G. E., and Ellis, L. M., Cyclooxygenase-2 is up-regulated by interleukin-1 beta in human colorectal cancer cells via multiple signaling pathways. Cancer Res., 63, 3632-3636 (2003)
  76. Madrid, L. V., Mayo, M. W., Reuther, J. Y., and Baldwin, A. S., Jr., Akt stimulates the transactivation potential of the RelA/ p65 Subunit of NF-${\kappa}$B through utilization of the I${\kappa}$B kinase and activation of the mitogen-activated protein kinase p38. J. Biol. Chem., 276, 18934-18940 (2001) https://doi.org/10.1074/jbc.M101103200
  77. Marks, F., Muller-Decker, K., and Furstenberger, G., A causal relationship between unscheduled eicosanoid signaling and tumor development: cancer chemoprevention by inhibitors of arachidonic acid metabolism. Toxicology, 153, 11-26 (2000) https://doi.org/10.1016/S0300-483X(00)00301-2
  78. Martin, A. R., Villegas, I., La Casa, C., and de la Lastra, C. A., Resveratrol, a polyphenol found in grapes, suppresses oxidative damage and stimulates apoptosis during early colonic inflammation in rats. Biochem. Pharmacol., 67, 1399- 1410 (2004) https://doi.org/10.1016/j.bcp.2003.12.024
  79. Martinez, J. and Moreno, J. J., Effect of resveratrol, a natural polyphenolic compound, on reactive oxygen species and prostaglandin production. Biochem. Pharmacol., 59, 865-870 (2000) https://doi.org/10.1016/S0006-2952(99)00380-9
  80. Marx, J., Cancer research. Inflammation and cancer: the link grows stronger. Science, 306, 966-968 (2004) https://doi.org/10.1126/science.30.783.966
  81. Miller, C., Zhang, M., He, Y., Zhao, J., Pelletier, J. P., Martel- Pelletier, J., and Di Battista, J. A., Transcriptional induction of cyclooxygenase-2 gene by okadaic acid inhibition of phosphatase activity in human chondrocytes: co-stimulation of AP-1 and CRE nuclear binding proteins. J. Cell. Biochem., 69, 392-413 (1998) https://doi.org/10.1002/(SICI)1097-4644(19980615)69:4<392::AID-JCB2>3.0.CO;2-I
  82. Molina-Holgado, E., Ortiz, S., Molina-Holgado, F., and Guaza, C., Induction of COX-2 and $PGE_{2}$ biosynthesis by IL-1${\beta}$ is mediated by PKC and mitogen-activated protein kinases in murine astrocytes. Br. J. Pharmacol., 131, 152-159 (2000) https://doi.org/10.1038/sj.bjp.0703557
  83. Muller-Decker, K., Neufang, G., Berger, I., Neumann, M., Marks, F., and Furstenberger, G., Transgenic cyclooxygenase-2 overexpression sensitizes mouse skin for carcinogenesis. Proc. Natl. Acad. Sci. USA, 99, 12483-12488 (2002) https://doi.org/10.1073/pnas.192323799
  84. Murakami, A., Matsumoto, K., Koshimizu, K., and Ohigashi, H., Effects of selected food factors with chemopreventive properties on combined lipopolysaccharide- and interferongamma- induced I${\kappa}$B degradation in RAW264.7 macrophages. Cancer Lett., 195, 17-25 (2003) https://doi.org/10.1016/S0304-3835(03)00058-2
  85. Niederberger, E., Tegeder, I., Vetter, G., Schmidtko, A., Schmidt, H., Euchenhofer, C., Brautigam, L., Grosch, S., and Geisslinger, G., Celecoxib loses its anti-inflammatory efficacy at high doses through activation of NF-${\kappa}$B. FASEB J., 15, 1622-1624 (2001)
  86. Nugent, K. P., Farmer, K. C., Spigelman, A. D., Williams, C. B., and Phillips, R. K., Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br. J. Surg., 80, 1618-1619 (1993) https://doi.org/10.1002/bjs.1800801244
  87. Oshima, M., Dinchuk, J. E., Kargman, S. L., Oshima, H., Hancock, B., Kwong, E., Trzaskos, J. M., Evans, J. F., and Taketo, M. M., Suppression of intestinal polyposis in Apc $^{\delta716}$ knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell, 87, 803-809 (1996) https://doi.org/10.1016/S0092-8674(00)81988-1
  88. Oshima, M., Murai, N., Kargman, S., Arguello, M., Luk, P., Kwong, E., Taketo, M. M., and Evans, J. F., Chemoprevention of intestinal polyposis in the $Apc^{\delta716}$ mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor. Cancer Res., 61, 1733- 1740 (2001)
  89. Park, J. W., Choi, Y. J., Suh, S. I., and Kwon, T. K., Involvement of ERK and protein tyrosine phosphatase signaling pathways in EGCG-induced cyclooxygenase-2 expression in Raw 264.7 cells. Biochem. Biophys. Res. Commun., 286, 721-725 (2001) https://doi.org/10.1006/bbrc.2001.5415
  90. Park, K. K., Chun, K.-S., Lee, J.-M., Lee, S. S., and Surh, Y.-J., Inhibitory effects of [6]-gingerol, a major pungent principle of ginger, on phorbol ester-induced inflammation, epidermal ornithine decarboxylase activity and skin tumor promotion in ICR mice. Cancer Lett., 129, 139-144 (1998) https://doi.org/10.1016/S0304-3835(98)00081-0
  91. Park, K. K., Chun, K.-S., Yook, J. I., and Surh, Y.-J., Lack of tumor promoting activity of capsaicin, a principal pungent ingredient of red pepper, in mouse skin carcinogenesis. Anticancer Res., 18, 4201-4205 (1998)
  92. Park, K. K. and Surh, Y.-J., Effects of capsaicin on chemicallyinduced two-stage mouse skin carcinogenesis. Cancer Lett., 114, 183-184 (1997) https://doi.org/10.1016/S0304-3835(97)04657-0
  93. Park, O.-J. and Surh, Y.-J., Chemopreventive potential of epigallocatechin gallate and genistein: evidence from epidemiological and laboratory studies. Toxicol. Lett., 150, 43-56 (2004) https://doi.org/10.1016/j.toxlet.2003.06.001
  94. Pentland, A. P., Schoggins, J. W., Scott, G. A., Khan, K. N., and Han, R., Reduction of UV-induced skin tumors in hairless mice by selective COX-2 inhibition. Carcinogenesis, 20, 1939-1944 (1999) https://doi.org/10.1093/carcin/20.10.1939
  95. Pikarsky, E., Porat, R. M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E., and Ben-Neriah, Y., NF-${\kappa}$B functions as a tumour promoter in inflammation-associated cancer. Nature, 431, 461-466 (2004) https://doi.org/10.1038/nature02924
  96. Qiao, L., Kozoni, V., Tsioulias, G. J., Koutsos, M. I., Hanif, R., Shiff, S. J., and Rigas, B., Selected eicosanoids increase the proliferation rate of human colon carcinoma cell lines and mouse colonocytes in vivo. Biochim. Biophys. Acta, 1258, 215-223 (1995) https://doi.org/10.1016/0005-2760(95)00100-Q
  97. Rigas, B., Goldman, I. S., and Levine, L., Altered eicosanoid levels in human colon cancer. J. Lab. Clin. Med., 122, 518- 523 (1993)
  98. Sakurai, H., Chiba, H., Miyoshi, H., Sugita, T., and Toriumi, W., I${\kappa}$B kinases phosphorylate NF-${\kappa}$B p65 subunit on serine 536 in the transactivation domain. J. Biol. Chem., 274, 30353- 30356 (1999) https://doi.org/10.1074/jbc.274.43.30353
  99. Schreinemachers, D. M. and Everson, R. B., Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology, 5, 138-146 (1994) https://doi.org/10.1097/00001648-199403000-00003
  100. Shao, J., Sheng, H., Inoue, H., Morrow, J. D., and DuBois, R. N., Regulation of constitutive cyclooxygenase-2 expression in colon carcinoma cells. J. Biol. Chem., 275, 33951-33956 (2000) https://doi.org/10.1074/jbc.M002324200
  101. Sheng, H., Shao, J., Dixon, D. A., Williams, C. S., Prescott, S. M., DuBois, R. N., and Beauchamp, R. D., Transforming growth factor-beta1 enhances Ha-ras-induced expression of cyclooxygenase-2 in intestinal epithelial cells via stabilization of mRNA. J. Biol. Chem., 275, 6628-6635 (2000) https://doi.org/10.1074/jbc.275.9.6628
  102. Sheng, H., Shao, J., and Dubois, R. N., K-Ras-mediated increase in cyclooxygenase 2 mRNA stability involves activation of the protein kinase B1. Cancer Res., 61, 2670- 2675 (2001)
  103. Sheng, H., Williams, C. S., Shao, J., Liang, P., DuBois, R. N., and Beauchamp, R. D., Induction of cyclooxygenase-2 by activated Ha-ras oncogene in Rat-1 fibroblasts and the role of mitogen-activated protein kinase pathway. J. Biol. Chem., 273, 22120-22127 (1998) https://doi.org/10.1074/jbc.273.34.22120
  104. Shishodia, S. and Aggarwal, B. B., Nuclear factor-${\kappa}$B: a friend or a foe in cancer? Biochem. Pharmacol., 68, 1071-1080 (2004) https://doi.org/10.1016/j.bcp.2004.04.026
  105. Shishodia, S., Koul, D., and Aggarwal, B. B., Cyclooxygenase (COX)-2 inhibitor celecoxib abrogates TNF-induced NF-${\kappa}$B activation through inhibition of activation of I${\kappa}$B${\alpha}$ kinase and Akt in human non-small cell lung carcinoma: correlation with suppression of COX-2 synthesis. J. Immunol., 173, 2011- 2022 (2004)
  106. Shishodia, S., Potdar, P., Gairola, C. G., and Aggarwal, B. B., Curcumin (diferuloylmethane) down-regulates cigarette smokeinduced NF-${\kappa}$B activation through inhibition of I${\kappa}$B${\alpha}$ kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1. Carcinogenesis, 24, 1269- 1279 (2003) https://doi.org/10.1093/carcin/bgg078
  107. Sizemore, N., Leung, S., and Stark, G. R., Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-${\kappa}$B p65/ RelA subunit. Mol. Cell Biol., 19, 4798-4805 (1999)
  108. Steinbach, G., Lynch, P. M., Phillips, R. K., Wallace, M. H., Hawk, E., Gordon, G. B., Wakabayashi, N., Saunders, B., Shen, Y., Fujimura, T., Su, L. K., and Levin, B., The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N. Engl. J. Med., 342, 1946-1952 (2000) https://doi.org/10.1056/NEJM200006293422603
  109. St-Germain, M. E., Gagnon, V., Mathieu, I., Parent, S., and Asselin, E., Akt regulates COX-2 mRNA and protein expression in mutated-PTEN human endometrial cancer cells. Int. J. Oncol., 24, 1311-1324 (2004a)
  110. St-Germain, M. E., Gagnon, V., Parent, S., and Asselin, E., Regulation of COX-2 protein expression by Akt in endometrial cancer cells is mediated through NF-${\kappa}$B/I${\kappa}$B pathway. Mol. Cancer., 3, 7 (2004b)
  111. Subbaramaiah, K., Altorki, N., Chung, W. J., Mestre, J. R., Sampat, A., and Dannenberg, A. J., Inhibition of cyclooxygenase- 2 gene expression by p53. J. Biol. Chem., 274, 10911-10915 (1999) https://doi.org/10.1074/jbc.274.16.10911
  112. Subbaramaiah, K., Chung, W. J., Michaluart, P., Telang, N., Tanabe, T., Inoue, H., Jang, M., Pezzuto, J. M., and Dannenberg, A. J., Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells. J. Biol. Chem., 273, 21875-21882 (1998) https://doi.org/10.1074/jbc.273.34.21875
  113. Subbaramaiah, K., Norton, L., Gerald, W., and Dannenberg, A. J., Cyclooxygenase-2 is overexpressed in HER-2/neupositive breast cancer: evidence for involvement of AP-1 and PEA3. J. Biol. Chem., 277, 18649-18657 (2002) https://doi.org/10.1074/jbc.M111415200
  114. Subbaramaiah, K., Zakim, D., Weksler, B. B., and Dannenberg, A. J., Inhibition of cyclooxygenase: a novel approach to cancer prevention. Proc. Soc. Exp. Biol. Med., 216, 201-210 (1997)
  115. Surh, Y.-J., Cancer chemoprevention with dietary phytochemicals. Nature Rev. Cancer, 3, 768-780 (2003) https://doi.org/10.1038/nrc1189
  116. Surh, Y.-J., Chun, K.-S., Cha, H.-H., Han, S.-S., Keum, Y.-S., Park, K.-K., and Lee, S.-S., Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-${\kappa}$B activation. Mutat. Res., 480-481, 243- 268 (2001)
  117. Surh, Y.-J., Han, S.-S., Keum, Y.-S., Seo, H.-J., and Lee, S.-S., Inhibitory effects of curcumin and capsaicin on phorbol esterinduced activation of eukaryotic transcription factors, NF-${\kappa}$B and AP-1. Biofactors, 12, 107-112 (2000) https://doi.org/10.1002/biof.5520120117
  118. Surh, Y.-J., Lee, R. C., Park, K.-K., Mayne, S. T., Liem, A., and Miller, J. A., Chemoprotective effects of capsaicin and diallyl sulfide against mutagenesis or tumorigenesis by vinyl carbamate and N-nitrosodimethylamine. Carcinogenesis, 16, 2467-2471 (1995) https://doi.org/10.1093/carcin/16.10.2467
  119. Surh, Y.-J. and Lee, S.-S., Capsaicin, a double-edged sword: toxicity, metabolism, and chemopreventive potential. Life Sci., 56, 1845-1855 (1995) https://doi.org/10.1016/0024-3205(95)00159-4
  120. Surh, Y.-J. and Lee, S.-S., Capsaicin in hot chili pepper: carcinogen, co-carcinogen or anticarcinogen? Food Chem. Toxicol., 34, 313-316 (1996) https://doi.org/10.1016/0278-6915(95)00108-5
  121. Surh, Y.-J., Na, H.-K., and Lee, S.-S., Transcription factors and mitogen-activated protein kinases as molecular targets for chemoprevention with anti-inflammatory phytochemicals. Biofactors, 21, 103-108 (2004) https://doi.org/10.1002/biof.552210119
  122. Takada, Y., Mukhopadhyay, A., Kundu, G. C., Mahabeleshwar, G. H., Singh, S., and Aggarwal, B. B., Hydrogen peroxide activates NF-${\kappa}$B through tyrosine phosphorylation of I${\kappa}$B${\alpha}$ and serine phosphorylation of p65: evidence for the involvement of IkBa kinase and Syk protein-tyrosine kinase. J. Biol. Chem., 278, 24233-24241 (2003) https://doi.org/10.1074/jbc.M212389200
  123. Takahashi, N., Tetsuka, T., Uranishi, H., and Okamoto, T., Inhibition of the NF-${\kappa}$B transcriptional activity by protein kinase A. Eur. J. Biochem., 269, 4559-4565 (2002) https://doi.org/10.1046/j.1432-1033.2002.03157.x
  124. Takeda, K., Kanekura, T., and Kanzaki, T., Negative feedback regulation of phosphatidylinositol 3-kinase/Akt pathway by over-expressed cyclooxygenase-2 in human epidermal cancer cells. J. Dermatol., 31, 516-523 (2004)
  125. Tang, Q., Gonzales, M., Inoue, H., and Bowden, G. T., Roles of Akt and glycogen synthase kinase 3beta in the ultraviolet B induction of cyclooxygenase-2 transcription in human keratinocytes. Cancer Res., 61, 4329-4332 (2001)
  126. Tiano, H. F., Loftin, C. D., Akunda, J., Lee, C. A., Spalding, J., Sessoms, A., Dunson, D. B., Rogan, E. G., Morham, S. G., Smart, R. C., and Langenbach, R., Deficiency of either cyclooxygenase (COX)-1 or COX-2 alters epidermal differentiation and reduces mouse skin tumorigenesis. Cancer Res., 62, 3395-3401 (2002)
  127. Tjandrawinata, R. R. and Hughes-Fulford, M., Up-regulation of cyclooxygenase-2 by product-prostaglandin $E_2$. Adv. Exp. Med. Biol., 407, 163-170 (1997)
  128. Tsujii, M. and DuBois, R. N., Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell, 83, 493-501 (1995) https://doi.org/10.1016/0092-8674(95)90127-2
  129. van Rees, B. P., Saukkonen, K., Ristimaki, A., Polkowski, W., Tytgat, G. N., Drillenburg, P., and Offerhaus, G. J., Cyclooxygenase- 2 expression during carcinogenesis in the human stomach. J. Pathol., 196, 171-179 (2002) https://doi.org/10.1002/path.1033
  130. Vanderveen, E. E., Grekin, R. C., Swanson, N. A., and Kragballe, K., Arachidonic acid metabolites in cutaneous carcinomas. Evidence suggesting that elevated levels of prostaglandins in basal cell carcinomas are associated with an aggressive growth pattern. Arch. Dermatol., 122, 407-412 (1986) https://doi.org/10.1001/archderm.122.4.407
  131. Verma, A. K., Ashendel, C. L., and Boutwell, R. K., Inhibition by prostaglandin synthesis inhibitors of the induction of epidermal ornithine decarboxylase activity, the accumulation of prostaglandins, and tumor promotion caused by 12-Otetradecanoylphorbol- 13-acetate. Cancer Res., 40, 308-315 (1980)
  132. Wang, D. and Baldwin, A. S., Jr., Activation of nuclear factorkappaB- dependent transcription by tumor necrosis factoralpha is mediated through phosphorylation of RelA/p65 on serine 529. J. Biol. Chem., 273, 29411-29416 (1998) https://doi.org/10.1074/jbc.273.45.29411
  133. Wang, H. Q., Kim, M. P., Tiano, H. F., Langenbach, R., and Smart, R. C., Protein kinase C-alpha coordinately regulates cytosolic phospholipase $A_{2}$ activity and the expression of cyclooxygenase-2 through different mechanisms in mouse keratinocytes. Mol. Pharmacol., 59, 860-866 (2001)
  134. Wang, X., Martindale, J. L., Liu, Y., and Holbrook, N. J., The cellular response to oxidative stress: influences of mitogenactivated protein kinase signalling pathways on cell survival. Biochem. J., 333 ( Pt 2), 291-300 (1998)
  135. Wesselborg, S., Bauer, M. K., Vogt, M., Schmitz, M. L., and Schulze-Osthoff, K., Activation of transcription factor NF-${\kappa}$B and p38 mitogen-activated protein kinase is mediated by distinct and separate stress effector pathways. J. Biol. Chem., 272, 12422-12429 (1997) https://doi.org/10.1074/jbc.272.19.12422
  136. Wilgus, T. A., Koki, A. T., Zweifel, B. S., Kusewitt, D. F., Rubal, P. A., and Oberyszyn, T. M., Inhibition of cutaneous ultraviolet light B-mediated inflammation and tumor formation with topical celecoxib treatment. Mol. Carcinog., 38, 49-58 (2003) https://doi.org/10.1002/mc.10141
  137. Wong, B. C., Jiang, X., Fan, X. M., Lin, M. C., Jiang, S. H., Lam, S. K., and Kung, H. F., Suppression of RelA/p65 nuclear translocation independent of I${\kappa}$B-${\alpha}$ degradation by cyclooxygenase- 2 inhibitor in gastric cancer. Oncogene, 22, 1189- 1197 (2003) https://doi.org/10.1038/sj.onc.1206234
  138. Wu, K. K., Aspirin and other cyclooxygenase inhibitors: new therapeutic insights. Semin. Vasc. Med., 3, 107-112 (2003) https://doi.org/10.1055/s-2003-40668
  139. Xie, W. and Herschman, H. R., v-src induces prostaglandin synthase 2 gene expression by activation of the c-Jun Nterminal kinase and the c-Jun transcription factor. J. Biol. Chem., 270, 27622-27628 (1995) https://doi.org/10.1074/jbc.270.46.27622
  140. Yan, X., Wu Xiao, C., Sun, M., Tsang, B. K., and Gibb, W., Nuclear factor ${\kappa}$B activation and regulation of cyclooxygenase type-2 expression in human amnion mesenchymal cells by interleukin-1${\beta}$. Biol. Reprod., 66, 1667-1671 (2002) https://doi.org/10.1095/biolreprod66.6.1667
  141. Yang, F., Tang, E., Guan, K., and Wang, C. Y., IKK beta plays an essential role in the phosphorylation of RelA/p65 on serine 536 induced by lipopolysaccharide. J. Immunol., 170, 5630-5635 (2003)
  142. Yip-Schneider, M. T., Barnard, D. S., Billings, S. D., Cheng, L., Heilman, D. K., Lin, A., Marshall, S. J., Crowell, P. L., Marshall, M. S., and Sweeney, C. J., Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. Carcinogenesis, 21, 139-146 (2000) https://doi.org/10.1093/carcin/21.2.139
  143. Yucel-Lindberg, T., Ahola, H., Carlstedt-Duke, J., and Modeer, T., Involvement of tyrosine kinases on cyclooxygenase expression and prostaglandin $E_2$ production in human gingival fibroblasts stimulated with interleukin-1beta and epidermal growth factor. Biochem. Biophys. Res. Commun., 257, 528-532 (1999) https://doi.org/10.1006/bbrc.1999.0523
  144. Zhong, H., Voll, R. E., and Ghosh, S., Phosphorylation of NF-${\kappa}$B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Mol. Cell, 1, 661-671 (1998) https://doi.org/10.1016/S1097-2765(00)80066-0
  145. Zhou, W., Jiang, Z. W., Tian, J., Jiang, J., Li, N., and Li, J. S., Role of NF-${\kappa}$B and cytokine in experimental cancer cachexia. World. J. Gastroenterol., 9, 1567-1570 (2003)
  146. Zweifel, B. S., Davis, T. W., Ornberg, R. L., and Masferrer, J. L., Direct evidence for a role of cyclooxygenase 2-derived prostaglandin $E_2$ in human head and neck xenograft tumors. Cancer Res., 62, 6706-6711 (2002)