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Celecoxib enhances the efficacy of 15-hydroxyprostaglandin dehydrogenase gene therapy in treating murine breast cancer

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Abstract

Purpose

The overexpression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has been proved to inhibit tumor growth and metastasis through degradation of prostaglandin E2 (PGE2), which is often overexpressed in various cancers and accelerates tumor progression. Cyclooxygenase-2 (COX-2), a synthase of PGE2, actively produces much PGE2 to counteract the 15-PGDH-induced antitumor efficacy. Here, we investigated the combinational effect by using pcDNA3.1(+) encoding mouse 15-PGDH gene therapy and celecoxib, a COX-2 inhibitor, in mouse breast cancers.

Methods

Mice bearing 4T1 were treated with short-term administration of the COX-2 inhibitor celecoxib (40 mg/kg/day) plus liposome-encapsulated mouse 15-PGDH in order to determine their synergistic antitumor activity in vivo. And the possible mechanisms were investigated.

Results

We observed that the combination treatment of 15-PGDH and celecoxib significantly inhibited tumor growth and lung metastases than monotherapy or controls. Moreover, the effect of combination treatment was associated with significant reduction of PGE2 in serum, which resulted from increased 15-PDGH and decreased COX-2 in tumor tissues. The tumor tissues in combination treatment presented more apoptotic cells and less microvessel density. Notably, the number of myeloid-derived suppressor cells in the spleen was also significantly decreased in the combination treatment than others.

Conclusions

Our findings suggested that celecoxib increased the antitumor activity of 15-PGDH by synergistically blocking PGE2 pathway, which might be a new feasible way for cancer therapy.

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References

  • Anderson BO, Yip CH, Ramsey SD, Bengoa R, Braun S, Fitch M, Groot M, Sancho-Garnier H, Tsu VD (2006) Breast cancer in limited-resource countries: health care systems and public policy. Breast J 12(Suppl 1):S54–S69

    Article  PubMed  Google Scholar 

  • Arico S, Pattingre S, Bauvy C, Gane P, Barbat A, Codogno P, Ogier-Denis E (2002) Celecoxib induces apoptosis by inhibiting 3-phosphoinositide-dependent protein kinase-1 activity in the human colon cancer HT-29 cell line. J Biol Chem 277(31):27613–27621

    Article  PubMed  CAS  Google Scholar 

  • Backlund MG, Mann JR, Holla VR, Buchanan FG, Tai HH, Musiek ES, Milne GL, Katkuri S, DuBois RN (2005) 15-Hydroxyprostaglandin dehydrogenase is down-regulated in colorectal cancer. J Biol Chem 280(5):3217–3223

    Article  PubMed  CAS  Google Scholar 

  • Basu GD, Pathangey LB, Tinder TL, Gendler SJ, Mukherjee P (2005) Mechanisms underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells. Breast Cancer Res 7(4):R422–R435

    Article  PubMed  CAS  Google Scholar 

  • Chang SH, Liu CH, Conway R, Han DK, Nithipatikom K, Trifan OC, Lane TF, Hla T (2004) Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. Proc Natl Acad Sci USA 101(2):591–596

    Article  PubMed  CAS  Google Scholar 

  • Chi X, Freeman BM, Tong M, Zhao Y, Tai HH (2009) 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is up-regulated by flurbiprofen and other non-steroidal anti-inflammatory drugs in human colon cancer HT29 cells. Arch Biochem Biophys 487(2):139–145

    Article  PubMed  CAS  Google Scholar 

  • Connolly EM, Harmey JH, O’Grady T, Foley D, Roche-Nagle G, Kay E, Bouchier-Hayes DJ (2002) Cyclo-oxygenase inhibition reduces tumour growth and metastasis in an orthotopic model of breast cancer. Br J Cancer 87(2):231–237

    Article  PubMed  CAS  Google Scholar 

  • Ding Y, Tong M, Liu S, Moscow JA, Tai HH (2005) NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer. Carcinogenesis 26(1):65–72

    Article  PubMed  CAS  Google Scholar 

  • Eruslanov E, Kaliberov S, Daurkin I, Kaliberova L, Buchsbaum D, Vieweg J, Kusmartsev S (2009) Altered expression of 15-hydroxyprostaglandin dehydrogenase in tumor-infiltrated CD11b myeloid cells: a mechanism for immune evasion in cancer. J Immunol 182(12):7548–7557

    Article  PubMed  CAS  Google Scholar 

  • Eruslanov E, Daurkin I, Ortiz J, Vieweg J, Kusmartsev S (2010) Pivotal advance: tumor-mediated induction of myeloid-derived suppressor cells and M2-polarized macrophages by altering intracellular PGE(2) catabolism in myeloid cells. J Leukoc Biol 88(5):839–848

    Article  PubMed  CAS  Google Scholar 

  • Frenkian M, Pidoux E, Baudoin C, Segond N, Jullienne A (2001a) Indomethacin increases 15-PGDH mRNA expression in HL60 cells differentiated by PMA. Prostaglandins Leukot Essent Fatty Acids 64(2):87–93

    Article  PubMed  CAS  Google Scholar 

  • Frenkian M, Segond N, Pidoux E, Cohen R, Jullienne A (2001b) Indomethacin, a COX inhibitor, enhances 15-PGDH and decreases human tumoral C cells proliferation. Prostaglandins 65(1):11–20

    Article  PubMed  CAS  Google Scholar 

  • Fujita M, Kohanbash G, Fellows-Mayle W, Hamilton RL, Komohara Y, Decker SA, Ohlfest JR, Okada H (2011) COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor cells. Cancer Res 71(7):2664–2674

    Article  PubMed  CAS  Google Scholar 

  • Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174

    Article  PubMed  CAS  Google Scholar 

  • Greenhough A, Smartt HJ, Moore AE, Roberts HR, Williams AC, Paraskeva C, Kaidi A (2009) The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 30(3):377–386

    Article  PubMed  CAS  Google Scholar 

  • Hahn T, Alvarez I, Kobie JJ, Ramanathapuram L, Dial S, Fulton A, Besselsen D, Walker E, Akporiaye ET (2006) Short-term dietary administration of celecoxib enhances the efficacy of tumor lysate-pulsed dendritic cell vaccines in treating murine breast cancer. Int J Cancer 118(9):2220–2231

    Article  PubMed  CAS  Google Scholar 

  • Harris RE, Alshafie GA, Abou-Issa H, Seibert K (2000) Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Cancer Res 60(8):2101–2103

    PubMed  CAS  Google Scholar 

  • Hulka BS, Moorman PG (2008) Breast cancer: hormones and other risk factors. Maturitas 61(1–2):203–213 discussion 213

    Article  PubMed  Google Scholar 

  • Jana NR (2008) NSAIDs and apoptosis. Cell Mol Life Sci 65(9):1295–1301

    Article  PubMed  CAS  Google Scholar 

  • Jemal A, Center MM, DeSantis C, Ward EM (2010) Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev 19(8):1893–1907

    Article  PubMed  Google Scholar 

  • Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90

    Article  PubMed  Google Scholar 

  • Jendrossek V (2011) Targeting apoptosis pathways by Celecoxib in cancer. Cancer Lett. doi:10.1016/j.canlet.2011.01.012

  • Kaliberova LN, Kusmartsev SA, Krendelchtchikova V, Stockard CR, Grizzle WE, Buchsbaum DJ, Kaliberov SA (2009) Experimental cancer therapy using restoration of NAD+-linked 15-hydroxyprostaglandin dehydrogenase expression. Mol Cancer Ther 8(11):3130–3139

    Article  PubMed  CAS  Google Scholar 

  • Khuder SA, Herial NA, Mutgi AB, Federman DJ (2005) Nonsteroidal antiinflammatory drug use and lung cancer: a metaanalysis. Chest 127(3):748–754

    Article  PubMed  Google Scholar 

  • Khuri FR, Wu H, Lee JJ, Kemp BL, Lotan R, Lippman SM, Feng L, Hong WK, Xu XC (2001) Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res 7(4):861–867

    PubMed  CAS  Google Scholar 

  • Leahy KM, Ornberg RL, Wang Y, Zweifel BS, Koki AT, Masferrer JL (2002) Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res 62(3):625–631

    PubMed  CAS  Google Scholar 

  • Leone V, di Palma A, Ricchi P, Acquaviva F, Giannouli M, Di Prisco AM, Iuliano F, Acquaviva AM (2007) PGE2 inhibits apoptosis in human adenocarcinoma Caco-2 cell line through Ras-PI3 K association and cAMP-dependent kinase A activation. Am J Physiol Gastrointest Liver Physiol 293(4):G673–G681

    Article  PubMed  CAS  Google Scholar 

  • Lou LH, Jing DD, Lai YX, Lu YY, Li JK, Wu K (2012) 15-PGDH is reduced and induces apoptosis and cell cycle arrest in gastric carcinoma. World J Gastroenterol 18(10):1028–1037

    Article  PubMed  CAS  Google Scholar 

  • Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, Edwards DA, Flickinger AG, Moore RJ, Seibert K (2000) Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60(5):1306–1311

    PubMed  CAS  Google Scholar 

  • Nagaraj S, Gabrilovich DI (2010) Myeloid-derived suppressor cells in human cancer. Cancer J 16(4):348–353

    Article  PubMed  CAS  Google Scholar 

  • Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182(8):4499–4506

    Article  PubMed  CAS  Google Scholar 

  • Patel MI, Subbaramaiah K, Du B, Chang M, Yang P, Newman RA, Cordon-Cardo C, Thaler HT, Dannenberg AJ (2005) Celecoxib inhibits prostate cancer growth: evidence of a cyclooxygenase-2-independent mechanism. Clin Cancer Res 11(5):1999–2007

    Article  PubMed  CAS  Google Scholar 

  • Reader J, Holt D, Fulton A (2011) Prostaglandin E2 EP receptors as therapeutic targets in breast cancer. Cancer Metastasis Rev 30(3–4):449–463

    Article  PubMed  CAS  Google Scholar 

  • Reddy BS, Hirose Y, Lubet R, Steele V, Kelloff G, Paulson S, Seibert K, Rao CV (2000) Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res 60(2):293–297

    PubMed  CAS  Google Scholar 

  • Ristimaki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C, Joensuu H, Isola J (2002) Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 62(3):632–635

    PubMed  CAS  Google Scholar 

  • Roche-Nagle G, Connolly EM, Eng M, Bouchier-Hayes DJ, Harmey JH (2004) Antimetastatic activity of a cyclooxygenase-2 inhibitor. Br J Cancer 91(2):359–365

    PubMed  CAS  Google Scholar 

  • Seno H, Oshima M, Ishikawa TO, Oshima H, Takaku K, Chiba T, Narumiya S, Taketo MM (2002) Cyclooxygenase 2- and prostaglandin E(2) receptor EP(2)-dependent angiogenesis in Apc(Delta716) mouse intestinal polyps. Cancer Res 62(2):506–511

    PubMed  CAS  Google Scholar 

  • Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S (2007) Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 67(9):4507–4513

    Article  PubMed  CAS  Google Scholar 

  • Tao K, Fang M, Alroy J, Sahagian GG (2008) Imagable 4T1 model for the study of late stage breast cancer. BMC Cancer 8:228

    Article  PubMed  Google Scholar 

  • Tatsuwaki H, Tanigawa T, Watanabe T, Machida H, Okazaki H, Yamagami H, Shiba M, Watanabe K, Tominaga K, Fujiwara Y, Oshitani N, Muguruma K, Sawada T, Hirakawa K, Higuchi K, Arakawa T (2010) Reduction of 15-hydroxyprostaglandin dehydrogenase expression is an independent predictor of poor survival associated with enhanced cell proliferation in gastric adenocarcinoma. Cancer Sci 101(2):550–558

    Article  PubMed  CAS  Google Scholar 

  • Veltman JD, Lambers ME, van Nimwegen M, Hendriks RW, Hoogsteden HC, Aerts JG, Hegmans JP (2010) COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function. BMC Cancer 10:464

    Article  PubMed  Google Scholar 

  • Wakimoto N, Wolf I, Yin D, O’Kelly J, Akagi T, Abramovitz L, Black KL, Tai HH, Koeffler HP (2008) Nonsteroidal anti-inflammatory drugs suppress glioma via 15-hydroxyprostaglandin dehydrogenase. Cancer Res 68(17):6978–6986

    Article  PubMed  CAS  Google Scholar 

  • Walker JD, Sehgal I, Kousoulas KG (2011) Oncolytic herpes simplex virus 1 encoding 15-prostaglandin dehydrogenase mitigates immune suppression and reduces ectopic primary and metastatic breast cancer in mice. J Virol 85(14):7363–7371

    Article  PubMed  CAS  Google Scholar 

  • Wang D, Dubois RN (2006) Prostaglandins and cancer. Gut 55(1):115–122

    Article  PubMed  CAS  Google Scholar 

  • Wang D, Dubois RN (2010a) Eicosanoids and cancer. Nat Rev Cancer 10(3):181–193

    Article  PubMed  CAS  Google Scholar 

  • Wang D, Dubois RN (2010b) The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene 29(6):781–788

    Article  PubMed  CAS  Google Scholar 

  • Wolf I, O’Kelly J, Rubinek T, Tong M, Nguyen A, Lin BT, Tai HH, Karlan BY, Koeffler HP (2006) 15-hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer. Cancer Res 66(15):7818–7823

    Article  PubMed  CAS  Google Scholar 

  • Yan M, Rerko RM, Platzer P, Dawson D, Willis J, Tong M, Lawrence E, Lutterbaugh J, Lu S, Willson JK, Luo G, Hensold J, Tai HH, Wilson K, Markowitz SD (2004) 15-Hydroxyprostaglandin dehydrogenase, a COX-2 oncogene antagonist, is a TGF-beta-induced suppressor of human gastrointestinal cancers. Proc Natl Acad Sci USA 101(50):17468–17473

    Article  PubMed  CAS  Google Scholar 

  • Yan M, Myung SJ, Fink SP, Lawrence E, Lutterbaugh J, Yang P, Zhou X, Liu D, Rerko RM, Willis J, Dawson D, Tai HH, Barnholtz-Sloan JS, Newman RA, Bertagnolli MM, Markowitz SD (2009) 15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors. Proc Natl Acad Sci USA 106(23):9409–9413

    Article  PubMed  CAS  Google Scholar 

  • Zhang N, Yang Y, Cheng L, Zhang XM, Zhang S, Wang W, Liu SY, Wang SY, Wang RB, Xu WJ, Dai L, Yan N, Fan P, Dai LX, Tian HW, Liu L, Deng HX (2012) Combination of Caspy2 and IP-10 gene therapy significantly improves therapeutic efficacy against murine malignant neoplasm growth and metastasis. Hum Gene Ther 23(8):837–846

    Article  PubMed  CAS  Google Scholar 

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Conflict of interest

There were no conflicts of interest associated with this work for any of the authors.

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Authors and Affiliations

  1. The Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, People’s Republic of China

    Binglan Zhang, Xuelei Ma, Lei Liu, Minmin Li & Jingyi Zhao

  2. State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, People’s Republic of China

    Zhimian Li, Xiang Gao, Fengtian Wang, Guobo Shen, Yaxiong Sang, Yuli Li & Yuquan Wei

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  1. Binglan Zhang
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  2. Xuelei Ma
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  3. Zhimian Li
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Correspondence to Yuquan Wei.

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Supplementary material 1 (Supplementary Fig. 1. Weight of mice in each group)

432_2013_1381_MOESM2_ESM.tif

Supplementary material 2 (Supplementary Fig. 2. The expression of 15-PGDH in vitro. 4T1 cells were transfected with pcDNA3.1 vector and pcDNA3.1 encoding 15-PGDH using lipo2000(Invitrogen, San Diego, CA, USA). After 48 h, 4T1 cells were harvested for the detection of 15-PGDH expression by using western blot)

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Zhang, B., Ma, X., Li, Z. et al. Celecoxib enhances the efficacy of 15-hydroxyprostaglandin dehydrogenase gene therapy in treating murine breast cancer. J Cancer Res Clin Oncol 139, 797–807 (2013). https://doi.org/10.1007/s00432-013-1381-9

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  • DOI: https://doi.org/10.1007/s00432-013-1381-9

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