Cancer and Metastasis Reviews

, Volume 30, Issue 3–4, pp 409–417 | Cite as

Prostaglandin catabolic enzymes as tumor suppressors

  • Hsin-Hsiung TaiEmail author


15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a key prostaglandin catabolic enzyme catalyzing the oxidation and inactivation of prostaglandin E2 (PGE2) synthesized from the cyclooxygenase (COX) pathway. Accumulating evidence indicates that 15-PGDH may function as a tumor suppressor antagonizing the action of COX-2 oncogene. 15-PGDH has been found to be down-regulated contributing to elevated levels of PGE2 in most tumors. The expression of 15-PGDH and COX-2 appears to be regulated reciprocally in cancer cells. Down-regulation of 15-PGDH in tumors is due, in part, to transcriptional repression and epigenetic silencing. Numerous agents have been found to up-regulate 15-PGDH by down-regulation of transcriptional repressors and by attenuation of the turnover of the enzyme. Up-regulation of 15-PGDH may provide a viable approach to cancer chemoprevention. Further catabolism of 15-keto-prostaglandin E2 is catalyzed by 15-keto-prostaglandin-∆13-reductase (13-PGR), which also exhibits LTB4-12-hydroxydehydrogenase (LTB4-12-DH) activity. 13-PGR/LTB4-12-DH behaves as a tumor suppressor as well. This review summarizes current knowledge of the expression and function of 15-PGDH and 13-PGR/LTB4-12-DH in lung and other tissues during tumor progression. Future directions of research on these prostaglandin catabolic enzymes as tumor suppressors are also discussed.


Prostaglandin dehydrogenase Prostaglandin reductase Cyclooxygenase Prostanoids Tumor suppressor Cancer chemoprevention 



I thank the support of the National Institutes of Health (HL-46296) and the Kentucky Lung Cancer Research Program for our work cited in this review.


  1. 1.
    Smith, W. L., DeWitt, D. L., & Garavito, R. M. (2000). Cyclooxygenases: Structural, cellular and molecular biology. Annual Review of Biochemistry, 69, 145–182.PubMedCrossRefGoogle Scholar
  2. 2.
    Tai, H. H., Cho, H., Tong, M., & Ding, Y. F. (2006). 15-Hydroxyprostaglandin dehydrogenase: Structure and biological functions. Current Pharmaceutical Design, 12, 955–962.PubMedCrossRefGoogle Scholar
  3. 3.
    Wang, D., & DuBois, R. N. (2006). Prostaglandins and cancer. Gut, 55, 115–122.PubMedCrossRefGoogle Scholar
  4. 4.
    Muller-Deeker, K., & Furstenberger, G. (2007). The cyclooxygenase-2-mediated prostaglandin signaling is casually related to epithelial carcinogenesis. Molecular Carcinogenesis, 46, 705–710.CrossRefGoogle Scholar
  5. 5.
    Celis, J. E., Ostergaard, M., Basse, B., Celis, A., Lauridsen, J. B., Ratz, G. P., et al. (1996). Loss of adipocyte-type fatty acid binding protein and other protein biomarkers is associated with progress of human bladder transitional carcinoma. Cancer Research, 56, 4782–4790.PubMedGoogle Scholar
  6. 6.
    Gee, J. R., MOntaya, R. G., Khaled, H. M., Sabichi, A. L., & Grossman, H. B. (2003). Cytokeratin 20, AN43, PGDH and COX-2 expression in transitional and squamous cell carcinoma of the bladder. Urological Oncology, 21, 266–270.Google Scholar
  7. 7.
    Tseng-Rogenski, S., Gee, J., Ignatoski, K. W., Kunju, L. P., Bucheit, A., Kinter, H. J., et al. (2010). Loss of 15-hydroxyprostaglandin dehydrogenase expression contributes to bladder cancer progression. American Journal of Pathology, 176, 1462–1468.PubMedCrossRefGoogle Scholar
  8. 8.
    Ding, Y., Tong, M., Liu, S., Moskow, J. A., & Tai, H. H. (2005). NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer. Carcinogenesis, 26, 65–72.PubMedCrossRefGoogle Scholar
  9. 9.
    Yang, L., Amann, J. M., Kikuchi, T., Porta, R., Guix, M., Gonzalez, A., et al. (2007). Inhibition of epidermal growth factor receptor signaling elevates 15-hydroxyprostaglandin dehydrogenase in non-small-cell lung cancer. Cancer Research, 67, 5587–5593.PubMedCrossRefGoogle Scholar
  10. 10.
    Hughes, D., Otani, Y., Yang, P., Newman, R. A., Yantiss, R. K., Altarki, N. K., et al. (2008). NAD+-dependent 15-hydroxyprostaglandin dehydrogenase regulates levels of bioactive lipids in non-small-cell lung cancer. Cancer Prevention Research, 1, 241–249.PubMedCrossRefGoogle Scholar
  11. 11.
    Yan, M., Rerko, R. M., Platzer, P., Dawson, D., Willis, J., Tong, M., et al. (2004). 15-Hydroxyprostaglandin dehydrogenase, a COX-2 antagonist, is a TGF-β-induced suppressor of human gastrointestinal cancers. Proceedings of the National Academy of Sciences of the United States of America, 10, 17468–17473.CrossRefGoogle Scholar
  12. 12.
    Backlund, M. G., Mann, J. R., Holla, V. R., Buchanan, F. G., Tai, H. H., Musiek, E. S., et al. (2005). 15-Hydroxyprostaglandin dehydrogenase is down-regulated in colorectal cancer. Journal of Biological Chemistry, 280, 3217–3223.PubMedCrossRefGoogle Scholar
  13. 13.
    Wolf, I., Okelly, J., Rubinek, T., Tong, M., Nguyen, A., Lin, B. T., et al. (2006). 15-Hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer. Cancer Research, 66, 7818–7823.PubMedCrossRefGoogle Scholar
  14. 14.
    Thill, M., Fischer, D., Hollen, F., Kelling, K., Dittmer, C., Landt, S., et al. (2010). Prostaglandin metabolizing enzymes and PGE2 are inversely correlated with vitamin D receptor and 25(OH)2D3 in breast cancer. Anticancer Research, 30, 1673–1679.PubMedGoogle Scholar
  15. 15.
    Celis, J. E., Gromov, P., Cabezon, T., Moreia, J. M. A., Friis, E., Jirstrom, K., et al. (2008). 15-Hydroxyprostaglandin dehydrogenase alone or in combination with ACSM1 defines a subgroup of the apocrine molecular subtype of breast carcinoma. Molecular & Cellular Proteomics, 7, 1795–1809.CrossRefGoogle Scholar
  16. 16.
    Thill, M., Fischer, D., KElling, K., Hoellen, F., Dittmer, C., Hornemann, A., et al. (2010). Expression of vitamin D receptor (VDR), cylcooxygenase-2 (COX-2) and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in benign and malignant ovarian tissue and 25-hydroxycholecaliferol (25(OH)2D3) and prostaglandin E2 (PGE2) serum level in ovarian cancer patients. The Journal of Steroid Biochemistry and Molecular Biology, 121, 387–390.PubMedCrossRefGoogle Scholar
  17. 17.
    Liu, Z., Wang, X., Lu, Y., Han, S., Zhang, F., Zhai, H., et al. (2008). Expression of 15-PGDH is down-regulated by COX-2 in gastric cancer. Carcinogenesis, 29, 1219–1227.PubMedCrossRefGoogle Scholar
  18. 18.
    Thiel, A., Ganesan, A., Mrena, J., Junnila, S., Nykanen, A., Hemmes, A., et al. (2009). 15-Hydroxyprostaglandin dehydrogenase is down-regulated in gastric cancer. Clinical Cancer Research, 15, 4572–4580.PubMedCrossRefGoogle Scholar
  19. 19.
    Tatsuwaki, H., Tanigawa, T., Watanabe, T., Machida, H., Okazaki, H., Yamagami, H., et al. (2010). Reduction of 15-hydroxyprostaglandin dehydrogenase expression is an independent predictor of poor survival associated with enhanced cell proliferation in gastric adenocarcinoma. Cancer Science, 101, 550–558.PubMedCrossRefGoogle Scholar
  20. 20.
    Song, H. J., Myung, S. J., Kim, I. W., Jeong, J. Y., Park, Y. S., Lee, S. M., et al. (2011). 15-Hydroxyprostaglandin dehydrogenase is down-regulated and exhibits tumor suppressor activity in gastric cancer. Cancer Investigation, 29, 257–265.PubMedCrossRefGoogle Scholar
  21. 21.
    Yoo, N. J., Jeong, E. G., & Lee, S. H. (2007). Expression of 15-hydroxyprostaglandin dehydrogenase, a COX-2 antagonist and tumor suppressor is not altered in gastric carcinomas. Pathology, 39, 174–175.PubMedCrossRefGoogle Scholar
  22. 22.
    Pham, H., Chen, M., Li, A., King, J., Angst, E., Dawson, D. W., et al. (2010). Loss of 15-hydroxyprostagalndin dehydrogenase increases prostaglandin E2 in pancreatic tumors. Pancreas, 39, 332–339.PubMedCrossRefGoogle Scholar
  23. 23.
    Hoeft, B., Linseisen, J., Beckmann, L., Muller-Decker, K., Canzian, F., Husing, A., et al. (2010). Polymorphisms in fatty acid metabolism-related genes are associated with colorectal cancer risk. Carcinogenesis, 31, 466–472.PubMedCrossRefGoogle Scholar
  24. 24.
    Otani, T., Yamaguchi, K., Schere, E., Du, B., Tai, H. H., Greifer, M., et al. (2006). Levels of NAD+-dependent 15-hydroxyprostaglandin dehydrogenase are reduced in inflammatory bowel disease: evidence for involvement of TNF-α. American Journal of Physiology, 290, G361–368.PubMedGoogle Scholar
  25. 25.
    Lousse, J. C., Defrere, S., Colette, S., Van Langendonckt, A., & Dormez, J. (2010). Expression of eicosanoid biosynthetic and catabolic enzymes in peritoneal endometriosis. Human Reproduction, 25, 734–741.PubMedCrossRefGoogle Scholar
  26. 26.
    Judson, B. L., Miyaki, A., Kekatpure, V. D., Du, B., Gilleaudeau, P., Sullivan-Whalen, M., et al. (2010). UV radiation inhibits 15-hydroxyprostaglandin dehydrogenase levels in human skin: evidence of transcriptional suppression. Cancer Prevention Research, 3, 1104–1111.PubMedCrossRefGoogle Scholar
  27. 27.
    Uppal, S., Diggle, C. P., Carr, I. M., Fishwick, C. W., Ahmed, M., Ibrahim, G. H., et al. (2008). Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nature Genetics, 40, 789–793.PubMedCrossRefGoogle Scholar
  28. 28.
    Tong, M., Ding, Y., & Tai, H. H. (2007). Reciprocal regulation of cyclooxygenase-2 and 15-hydroxyprostaglandin dehydrogenase expression in A549 human lung adenocarcinoma cells. Carcinogenesis, 27, 2170–2179.CrossRefGoogle Scholar
  29. 29.
    Lennon, C., Carlson, M. G., Nelson, D. M., & Sadovsky, Y. (1999). In vitro modulation of the expression of 15-hydroxyprostaglandin dehydrogenase by trophoblast differentiation. American Journal of Obstetrics and Gynecology, 180, 690–695.PubMedCrossRefGoogle Scholar
  30. 30.
    Moreno, J., Krishnan, A. V., Swami, S., Nonn, I., Peehl, D. M., & Feldman, D. (2005). Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Research, 65, 7919–7925.CrossRefGoogle Scholar
  31. 31.
    Krishnan, A. V., Swami, S., & Feldman, D. (2010). Vitamin D and breast cancer: Inhibition of estrogen synthesis and signaling. The Journal of Steroid Biochemistry and Molecular Biology, 121, 343–348.PubMedCrossRefGoogle Scholar
  32. 32.
    Lim, K., Han, C., Xu, L., Isse, K., Demetris, A. J., & Wu, T. (2008). Cyclooxygenase-2-derived prostaglandin E2 activates β-catenin in human cholangiocarcinoma cells: Evidence for inhibition of these signaling pathways by ω3 polyunsaturated fatty acids. Cancer Research, 68, 553–560.PubMedCrossRefGoogle Scholar
  33. 33.
    Lim, K., Han, C., Dai, Y., Shen, M., & Wu, T. (2009). Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking β-catenin and cylcooxygenase-2. Molecular Cancer Therapeutics, 8, 3046–3055.PubMedCrossRefGoogle Scholar
  34. 34.
    Brecht, K., Weigert, A., Hu, J., Popp, R., Fisslthaler, B., Korff, T., et al. (2011). Macrophages programmed by apoptotic cells promote angiogenesis via prostaglandin E2. The FASEB Journal, 25, 2408–2417.PubMedCrossRefGoogle Scholar
  35. 35.
    Eruslanov, E., Daurkin, I., Ortiz, J., Vieweg, J., & Kusmartsev, S. (2010). Tumor-mediated induction of myeloid-derived suppressor cells and M2-polarized macrophages by altering intracellular PGE2 catabolism in myeloid cells. Journal of Leukocyte Biology, 88, 839–848.PubMedCrossRefGoogle Scholar
  36. 36.
    Eruslanov, E., Kaliberov, S., Daurkin, I., Kaliberova, L., Buchabaam, D., Vieweg, J., et al. (2009). Altered expression of 15-hydroxyprostaglandin dehydrogenase in tumor-infiltrated CD11b myeloid cells: A mechanism for immune evasion in cancer. Journal of Immunology, 182, 7548–7557.CrossRefGoogle Scholar
  37. 37.
    Kaliberova, L. N., Kusmartsev, S. A., Kredelcht-Chikova, V., Stockard, C. R., Grizzle, W. E., Buchsbaum, D. J., et al. (2009). Experimental cancer therapy using restoration of NAD+-linked 15-hydroxyprostaglandin dehydrogenase expression. Molecular Cancer Therapeutics, 8, 3130–3139.PubMedCrossRefGoogle Scholar
  38. 38.
    Li, M., Xie, J., Cheng, L., Chang, B., Wang, Y., Lan, X., et al. (2008). Suppression of invasive properties of colorectal carcinoma SW480 cells by 15-hydroxyprostaglandin dehydrogenase gene. Cancer Investigation, 26, 905–912.PubMedCrossRefGoogle Scholar
  39. 39.
    Myung, S., Rerko, R. M., Yan, M., Platzer, P., Guda, K., Dotson, A., et al. (2006). 15-Hydroxyprostaglandin dehydrogenase is an in vivo suppressor of colon tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America, 103, 12098–12102.PubMedCrossRefGoogle Scholar
  40. 40.
    Yan, M., Myung, S. J., Fink, S. P., Lawrence, E., Lutterbaugh, J., et al. (2009). 15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors. Proceedings of the National Academy of Sciences of the United States of America, 106, 9409–9413.PubMedCrossRefGoogle Scholar
  41. 41.
    Greenland, K. J., Jantke, I., Jenatschke, S., Bracken, K. E., Vinson, C., & Gellersen, B. (2000). The human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase gene promote is controlled by Ets and activating protein-1 transcriptional factors and progesterone. Endocrinology, 141, 581–597.PubMedCrossRefGoogle Scholar
  42. 42.
    Mann, J. R., Backlund, M. G., Buchanan, F. G., Daikoku, T., Holla, V. R., Rosen berg, D. W., et al. (2006). Repression of prostaglandin dehydrogenase by epidermal growth factor and snail increases prostaglandin E2 and promotes cancer progression. Cancer Research, 66, 6649–6656.PubMedCrossRefGoogle Scholar
  43. 43.
    Backlund, M. G., Mann, J. R., Holla, V. R., Shi, Q., Daikoku, T., Dey, S. K., et al. (2008). Repression of 15-hydroxyprostaglandin dehydrogenase involved histone deacetylase 2 and snail in colorectal cancer. Cancer Research, 68, 9331–9337.PubMedCrossRefGoogle Scholar
  44. 44.
    Tong, M., Ding, Y., & Tai, H. H. (2006). Histone deacetylase inhibitors and transforming growth factor-β induce 15-hydroxyprostaglandin dehydrogenase expression in human lung adenocarcinoma cells. Biochemical Pharmacology, 72, 701–709.PubMedCrossRefGoogle Scholar
  45. 45.
    Chi, X., Freeman, B. M., Tong, M., Zhao, Y., & Tai, H. H. (2009). 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is up-regulated by flurbiprofen and other non-steroidal anti-inflammatory drugs in human colon cancer H29 cells. Archives of Biochemistry and Biophysics, 487, 139–145.PubMedCrossRefGoogle Scholar
  46. 46.
    Lodygin, D., Epanchintsev, A., Menssen, A., Diebold, J., & Hermeking, H. (2005). Functional epigenomics identifies genes frequently silenced in prostate cancer. Cancer Research, 65, 4218–4227.PubMedCrossRefGoogle Scholar
  47. 47.
    Marnett, L. J. (2009). Mechanisms of cyclooxygenase-2 inhibition and cardiovascular side effects—The plot thickens. Cancer Prevention Research, 2, 288–290.PubMedCrossRefGoogle Scholar
  48. 48.
    Cha, Y., & DuBois, R. N. (2007). NSAIDs and cancer prevention: Targets downstream of COX-2. Annual Review of Medicine, 58, 239–252.PubMedCrossRefGoogle Scholar
  49. 49.
    Dubinett, S. M., Mao, J. T., & Hazra, S. (2008). Focusing downstream in lung cancer prevention: 15-Hydroxyprostaglandin dehydrogenase. Cancer Prevention Research, 1, 223–225.PubMedCrossRefGoogle Scholar
  50. 50.
    Markowitz, S. D. (2008). Colorectal neoplasia goes with the flow: Prostaglandin transport and termination. Cancer Prevention Research, 1, 77–79.PubMedCrossRefGoogle Scholar
  51. 51.
    Tong, M., & Tai, H. H. (2005). 15-Hydroxyprostaglandin dehydrogenase can be induced by dexamethasone and other glucocorticoids at the therapeutic level in A549 human lung adenocarcinoma cells. Archives of Biochemistry and Biophysics, 435, 50–55.PubMedCrossRefGoogle Scholar
  52. 52.
    Frenkian, M., Pidoux, E., Baudoin, C., Segond, N., & Jullienne, A. (2001). Indomethacin increases 15-PGDH expression in HL60 cells differentiated by PMA. Prostaglandins, Leukotrienes, and Essential Fatty Acids, 64, 87–93.PubMedCrossRefGoogle Scholar
  53. 53.
    Frenkian, M., Segond, N., Pidoux, E., Cohen, R., & Jullienne, A. (2001). Indomethacin, a COX inhibitor, enhances 15-PGDH and decreases human tumerol C cells proliferation. Prostaglandins & Other Lipid Mediators, 65, 11–20.CrossRefGoogle Scholar
  54. 54.
    Wakimoto, N., Wolf, I., Yin, D., O’Kelly, J., Akagi, T., Abramovitz, L., et al. (2008). Nonsteroidal anti-inflammatory drugs suppress glioma via 15-hydroxyprostaglandin dehydrogenase. Cancer Research, 68, 6978–6986.PubMedCrossRefGoogle Scholar
  55. 55.
    Tai, H. H., Chi, X. & Tong, M. (2011) Regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) by non-steroidal anti-inflammatory drugs (NSAIDs). Prostaglandins and Other Lipid Mediators (in press).Google Scholar
  56. 56.
    Hazra, S., Batra, R. K., Tai, H. H., Sharma, S., Cui, X., & Dubinett, S. M. (2007). Pioglitazone and rosiglitazone decrease prostaglandin E2 in non-small-cell lung cancer cells by up-regulating 15-hydroxyprostaglandin dehydrogenase. Molecular Pharmacology, 71, 1715–1720.PubMedCrossRefGoogle Scholar
  57. 57.
    Krishnan, A. V., Srinivas, S., & Feldman, D. (2009). Inhibition of prostaglandin synthesis and actions contributes to the beneficial effects of calcitriol in prostate cancer. Dermato-Endocrinology, 1, 7–11.PubMedCrossRefGoogle Scholar
  58. 58.
    Singh, R. P., Gu, M., & Agarwal, R. (2008). Silibilin inhibits colorectal cancer growth by inhibiting tumor cell proliferation and angiogenesis. Cancer Research, 68, 2043–2050.PubMedCrossRefGoogle Scholar
  59. 59.
    Spinola, M., Colombo, F., Falvella, S., & Dragani, T. A. (2007). N6-Isopentenyladenosine: A potential therapeutic agent for a variety of epithelial cancers. International Journal of Cancer, 120, 2744–2748.CrossRefGoogle Scholar
  60. 60.
    Chi, X., & Tai, H. H. (2010). Interleukin-4 up-regulates 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in human lung cancer cells. Experimental Cell Research, 316, 2251–2259.PubMedCrossRefGoogle Scholar
  61. 61.
    Harding, L., Wang, Z., & Tai, H. H. (1996). Stimulation of prostaglandin E2 synthesis by interleukin-1β is amplified by interferons but inhibited by interleukin-4 in human amnion-derived WISH cells. Biochimica et Biophysica Acta, 1310, 48–52.PubMedCrossRefGoogle Scholar
  62. 62.
    Cui, X., Yang, S. C., Sharma, S., Heuze-vourch, N., & Dubinett, S. M. (2006). IL-4 regulates COX-2 and PGE2 production in human non-small-cell lung cancer. Biochemical and Biophysical Research Communications, 343, 995–1001.PubMedCrossRefGoogle Scholar
  63. 63.
    Huang, G., Eisenberg, R., Yan, M., Monti, S., Lawrence, E., Fu, P., et al. (2008). 15-Hydroxyprostaglandin dehydrogenase is a target of heptocyte nuclear factor 3β and a tumor suppressor in lung cancer. Cancer Research, 68, 5040–5048.PubMedCrossRefGoogle Scholar
  64. 64.
    Nomura, T., Lu, R., Satriano, J. A., et al. (2004). The two-step model of prostaglandin signal termination: In vitro reconstitution with the prostaglandin transporter and prostaglandin 15-dehydrogenase. Molecular Pharmacology, 65, 973–978.PubMedCrossRefGoogle Scholar
  65. 65.
    Holla, V. R., Backlund, M. G., Yang, P., Newman, R. A., & DuBois, R. N. (2008). Regulation of prostaglandin transporters in colorectal neoplasia. Cancer Prevention Research, 1, 93–99.PubMedCrossRefGoogle Scholar
  66. 66.
    Zhao, Y., Weng, C. C., Tong, M., Wei, J., & Tai, H. H. (2010). Restoration of leukotriene B4-12-hydroxydehydrogenase/15-oxo-prostaglandin 13-reductase expression inhibits lung cancer growth in vitro and in vivo. Lung Cancer, 68, 161–169.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, College of PharmacyUniversity of KentuckyLexingtonUSA

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