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Published in:

01-12-2011

Prostaglandin catabolic enzymes as tumor suppressors

Author: Hsin-Hsiung Tai

Published in: Cancer and Metastasis Reviews | Issue 3-4/2011

Abstract

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.

Smith, W. L., DeWitt, D. L., & Garavito, R. M. (2000). Cyclooxygenases: Structural, cellular and molecular biology. Annual Review of Biochemistry, 69, 145–182.PubMedCrossRef

Tai, H. H., Cho, H., Tong, M., & Ding, Y. F. (2006). 15-Hydroxyprostaglandin dehydrogenase: Structure and biological functions. Current Pharmaceutical Design, 12, 955–962.PubMedCrossRef

Wang, D., & DuBois, R. N. (2006). Prostaglandins and cancer. Gut, 55, 115–122.PubMedCrossRef

Muller-Deeker, K., & Furstenberger, G. (2007). The cyclooxygenase-2-mediated prostaglandin signaling is casually related to epithelial carcinogenesis. Molecular Carcinogenesis, 46, 705–710.CrossRef

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.PubMed

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.

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

47.

Marnett, L. J. (2009). Mechanisms of cyclooxygenase-2 inhibition and cardiovascular side effects—The plot thickens. Cancer Prevention Research, 2, 288–290.PubMedCrossRef

48.

Cha, Y., & DuBois, R. N. (2007). NSAIDs and cancer prevention: Targets downstream of COX-2. Annual Review of Medicine, 58, 239–252.PubMedCrossRef

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.PubMedCrossRef

50.

Markowitz, S. D. (2008). Colorectal neoplasia goes with the flow: Prostaglandin transport and termination. Cancer Prevention Research, 1, 77–79.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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).

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

Title: Prostaglandin catabolic enzymes as tumor suppressors
Author: Hsin-Hsiung Tai
Publication date: 01-12-2011
Publisher: Springer US
Published in: Cancer and Metastasis Reviews / Issue 3-4/2011
Print ISSN: 0167-7659
Electronic ISSN: 1573-7233
DOI: https://doi.org/10.1007/s10555-011-9314-z

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