Original Communication| Volume 144, ISSUE 1, P57-65, July 2008

Mononuclear cell-derived interleukin-1 beta confers chemoresistance in pancreatic cancer cells by upregulation of cyclooxygenase-2

  • Eliane Angst
    Hirshberg Laboratories for Pancreatic Cancer Research, CURE: Digestive Diseases Research Center, David Geffen School of Medicine at UCLA, Los Angeles, Calif

    Department of Visceral and Transplant Surgery, University Hospital, Berne, Switzerland
    Search for articles by this author
  • Howard A. Reber
    Hirshberg Laboratories for Pancreatic Cancer Research, CURE: Digestive Diseases Research Center, David Geffen School of Medicine at UCLA, Los Angeles, Calif

    Department of Surgery, CURE: Digestive Diseases Research Center, David Geffen School of Medicine at UCLA, Los Angeles, Calif
    Search for articles by this author
  • Oscar J. Hines
    Hirshberg Laboratories for Pancreatic Cancer Research, CURE: Digestive Diseases Research Center, David Geffen School of Medicine at UCLA, Los Angeles, Calif

    Department of Surgery, CURE: Digestive Diseases Research Center, David Geffen School of Medicine at UCLA, Los Angeles, Calif
    Search for articles by this author
  • Guido Eibl
    Reprint requests: Guido Eibl, MD, Department of Surgery, David Geffen School of Medicine at UCLA, 675 Charles E. Young Drive South, MRL 2535, Los Angeles, CA 90095.
    Hirshberg Laboratories for Pancreatic Cancer Research, CURE: Digestive Diseases Research Center, David Geffen School of Medicine at UCLA, Los Angeles, Calif

    Department of Surgery, CURE: Digestive Diseases Research Center, David Geffen School of Medicine at UCLA, Los Angeles, Calif
    Search for articles by this author


      Pancreatic cancer is a very aggressive malignancy and efficient therapeutic options are still largely lacking. The importance of interactions between tumor cells and surrounding stromal elements, eg, mononuclear cells, for chemoresistance have been increasingly recognized. In addition, cyclooxygenase-2 is thought to be an important mediator of chemoresistance in several malignancies. The aim of this study was to explore the role of mononuclear cells in pancreatic cancer chemoresistance.


      Human histiocytic lymphoma U937 cells were differentiated into macrophage-like cells. The effect of U937-conditioned medium on drug-induced pancreatic cancer cell apoptosis was measured by enzyme-linked immunosorbent assay. The contributions of interleukin-1β and cyclooxygenase-2 were evaluated by specific receptor antagonists and inhibitors. The importance of the extracellular signal-regulated kinase (ERK1/2) pathway also was determined.


      U937-conditioned culture medium protected pancreatic cancer cells from drug-induced apoptosis. This protective effect was abolished by an interleukin-1 receptor antagonist and cyclooxygenase-2 inhibitor. U937-conditioned medium and interleukin-1β stimulated expression of cyclooxygenase-2 and prostaglandin E2 production in pancreatic cancer cells, which was mediated by activation of the ERK1/2 pathway. Transfection of pancreatic cancer cells with cyclooxygenase-2 increased resistance to drug-induced cell death.


      Mononuclear cells protect pancreatic cancer cells from drug-induced apoptosis in vitro by interleukin-1β–mediated expression of cyclooxygenase-2 and production of prostaglandins. This study highlights the importance of tumor-host interactions in pancreatic cancers and may provide the basis for novel therapeutic approaches to sensitize pancreatic cancers to chemotherapeutic agents.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Bronte V.
        • Cingarlini S.
        • Marigo I.
        • De Santo C.
        • Gallina G.
        • Dolcetti L.
        • et al.
        Leukocyte infiltration in cancer creates an unfavorable environment for antitumor immune responses: a novel target for therapeutic intervention.
        Immunol Invest. 2006; 35: 327-357
        • Mahadevan D.
        • Von Hoff D.D.
        Tumor-stroma interactions in pancreatic ductal adenocarcinoma.
        Mol Cancer Ther. 2007; 6: 1186-1197
        • Pollard J.W.
        Tumour-educated macrophages promote tumour progression and metastasis.
        Nat Rev Cancer. 2004; 4: 71-78
        • Bellocq A.
        • Antoine M.
        • Flahault A.
        • Philippe C.
        • Crestani B.
        • Bernaudin J.F.
        • et al.
        Neutrophil alveolitis in bronchioloalveolar carcinoma: induction by tumor-derived interleukin-8 and relation to clinical outcome.
        Am J Pathol. 1998; 152: 83-92
        • Esposito I.
        • Menicagli M.
        • Funel N.
        • Bergmann F.
        • Boggi U.
        • Mosca F.
        • et al.
        Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma.
        J Clin Pathol. 2004; 57: 630-636
        • Emmrich J.
        • Sparmann G.
        • Hopt U.
        • Lohr M.
        • Liebe S.
        Typing of leukocytes in pancreatic tissue surrounding human pancreatic carcinoma.
        Ann N Y Acad Sci. 1999; 880: 171-174
        • Braddock M.
        • Quinn A.
        Targeting IL-1 in inflammatory disease: new opportunities for therapeutic intervention.
        Nat Rev Drug Discov. 2004; 3: 330-339
        • Martin M.U.
        • Wesche H.
        Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family.
        Biochim Biophys Acta. 2002; 1592: 265-280
        • Apte R.N.
        • Dotan S.
        • Elkabets M.
        • White M.R.
        • Reich E.
        • Carmi Y.
        • et al.
        The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions.
        Cancer Metastasis Rev. 2006; 25: 387-408
        • Dinarello C.A.
        The IL-1 family and inflammatory diseases.
        Clin Exp Rheumatol. 2002; 20: S1-S13
        • Wang D.
        • Dubois R.N.
        Prostaglandins and cancer.
        Gut. 2006; 55: 115-122
        • Nagai N.
        • Tian X.
        • Mukai K.
        • Hirata E.
        • Kusuda T.
        • Shiroyama Y.
        • et al.
        Overexpression of cyclooxygenase-2 protein and its relationship to apoptosis in cervical carcinoma treated with neoadjuvant chemotherapy.
        Int J Mol Med. 2003; 12: 709-714
        • Saikawa Y.
        • Sugiura T.
        • Toriumi F.
        • Kubota T.
        • Suganuma K.
        • Isshiki S.
        • et al.
        Cyclooxygenase-2 gene induction causes CDDP resistance in colon cancer cell line, HCT-15.
        Anticancer Res. 2004; 24: 2723-2728
        • Trifan O.C.
        • Hla T.
        Cyclooxygenase-2 modulates cellular growth and promotes tumorigenesis.
        J Cell Mol Med. 2003; 7: 207-222
        • Lau L.
        • Hansford L.M.
        • Cheng L.S.
        • Hang M.
        • Baruchel S.
        • Kaplan D.R.
        • et al.
        Cyclooxygenase inhibitors modulate the p53/HDM2 pathway and enhance chemotherapy-induced apoptosis in neuroblastoma.
        Oncogene. 2007; 26: 1920-1931
        • Zatelli M.C.
        • Luchin A.
        • Piccin D.
        • Tagliati F.
        • Bottoni A.
        • Vignali C.
        • et al.
        Cyclooxygenase-2 inhibitors reverse chemoresistance phenotype in medullary thyroid carcinoma by a permeability glycoprotein-mediated mechanism.
        J Clin Endocrinol Metab. 2005; 90: 5754-5760
        • Kokawa A.
        • Kondo H.
        • Gotoda T.
        • Ono H.
        • Saito D.
        • Nakadaira S.
        • et al.
        Increased expression of cyclooxygenase-2 in human pancreatic neoplasms and potential for chemoprevention by cyclooxygenase inhibitors.
        Cancer. 2001; 91: 333-338
        • Tucker O.N.
        • Dannenberg A.J.
        • Yang E.K.
        • Zhang F.
        • Teng L.
        • Daly J.M.
        • et al.
        Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer.
        Cancer Res. 1999; 59: 987-990
        • Juuti A.
        • Louhimo J.
        • Nordling S.
        • Ristimaki A.
        • Haglund C.
        Cyclooxygenase-2 expression correlates with poor prognosis in pancreatic cancer.
        J Clin Pathol. 2006; 59: 382-386
        • Eibl G.
        • Takata Y.
        • Boros L.G.
        • Liu J.
        • Okada Y.
        • Reber H.A.
        • et al.
        Growth stimulation of COX-2-negative pancreatic cancer by a selective COX-2 inhibitor.
        Cancer Res. 2005; 65: 982-990
        • Funahashi H.
        • Satake M.
        • Dawson D.
        • Huynh N.A.
        • Reber H.A.
        • Hines O.J.
        • et al.
        Delayed progression of pancreatic intraepithelial neoplasia in a conditional Kras(G12D) mouse model by a selective cyclooxygenase-2 inhibitor.
        Cancer Res. 2007; 67: 7068-7071
        • Sipos B.
        • Moser S.
        • Kalthoff H.
        • Torok V.
        • Lohr M.
        • Kloppel G.
        A comprehensive characterization of pancreatic ductal carcinoma cell lines: towards the establishment of an in vitro research platform.
        Virchows Arch. 2003; 442: 444-452
        • Larrick J.W.
        • Fischer D.G.
        • Anderson S.J.
        • Koren H.S.
        Characterization of a human macrophage-like cell line stimulated in vitro: a model of macrophage functions.
        J Immunol. 1980; 125: 6-12
        • Shin Y.H.
        • Lee G.W.
        • Son K.N.
        • Lee S.M.
        • Kang C.J.
        • Kwon B.S.
        • et al.
        Promoter analysis of human CC chemokine CCL23 gene in U937 monocytoid cells.
        Biochim Biophys Acta. 2007; 1769: 204-208
        • Eibl G.
        • Bruemmer D.
        • Okada Y.
        • Duffy J.P.
        • Law R.E.
        • Reber H.A.
        • et al.
        PGE(2) is generated by specific COX-2 activity and increases VEGF production in COX-2-expressing human pancreatic cancer cells.
        Biochem Biophys Res Commun. 2003; 306: 887-897
        • Okada Y.
        • Eibl G.
        • Guha S.
        • Duffy J.P.
        • Reber H.A.
        • Hines O.J.
        Nerve growth factor stimulates MMP-2 expression and activity and increases invasion by human pancreatic cancer cells.
        Clin Exp Metastasis. 2004; 21: 285-292
        • Sawai H.
        • Okada Y.
        • Kazanjian K.
        • Kim J.
        • Hasan S.
        • Hines O.J.
        • et al.
        The G691S RET polymorphism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling.
        Cancer Res. 2005; 65: 11536-11544
        • Janssens S.
        • Beyaert R.
        Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members.
        Mol Cell. 2003; 11: 293-302
        • Tsatsanis C.
        • Androulidaki A.
        • Venihaki M.
        • Margioris A.N.
        Signalling networks regulating cyclooxygenase-2.
        Int J Biochem Cell Biol. 2006; 38: 1654-1661
        • Muerkoster S.S.
        • Lust J.
        • Arlt A.
        • Hasler R.
        • Witt M.
        • Sebens T.
        • et al.
        Acquired chemoresistance in pancreatic carcinoma cells: induced secretion of IL-1beta and NO lead to inactivation of caspases.
        Oncogene. 2006; 25: 3973-3981
        • Covey J.M.
        • Jaxel C.
        • Kohn K.W.
        • Pommier Y.
        Protein-linked DNA strand breaks induced in mammalian cells by camptothecin, an inhibitor of topoisomerase I.
        Cancer Res. 1989; 49: 5016-5022
        • Sun F.X.
        • Tohgo A.
        • Bouvet M.
        • Yagi S.
        • Nassirpour R.
        • Moossa A.R.
        • et al.
        Efficacy of camptothecin analog DX-8951f (Exatecan Mesylate) on human pancreatic cancer in an orthotopic metastatic model.
        Cancer Res. 2003; 63: 80-85
        • Abou-Alfa G.K.
        • Letourneau R.
        • Harker G.
        • Modiano M.
        • Hurwitz H.
        • Tchekmedyian N.S.
        • et al.
        Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer.
        J Clin Oncol. 2006; 24: 4441-4447
        • Stathopoulos G.P.
        • Syrigos K.
        • Aravantinos G.
        • Polyzos A.
        • Papakotoulas P.
        • Fountzilas G.
        • et al.
        A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer.
        Br J Cancer. 2006; 95: 587-592
        • Buchler P.
        • Reber H.A.
        • Buchler M.
        • Shrinkante S.
        • Buchler M.W.
        • Friess H.
        • et al.
        Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer.
        Pancreas. 2003; 26: 56-64
        • Banerjee S.
        • Zhang Y.
        • Wang Z.
        • Che M.
        • Chiao P.J.
        • Abbruzzese J.L.
        • et al.
        In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer.
        Int J Cancer. 2007; 120: 906-917
        • El-Rayes B.F.
        • Ali S.
        • Ali I.F.
        • Philip P.A.
        • Abbruzzese J.
        • Sarkar F.H.
        Potentiation of the effect of erlotinib by genistein in pancreatic cancer: the role of Akt and nuclear factor-kappaB.
        Cancer Res. 2006; 66: 10553-10559
        • Banerjee S.
        • Zhang Y.
        • Ali S.
        • Bhuiyan M.
        • Wang Z.
        • Chiao P.J.
        • et al.
        Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer.
        Cancer Res. 2005; 65: 9064-9072
        • Garrelds I.M.
        • van Hal P.T.
        • Haakmat R.C.
        • Hoogsteden H.C.
        • Saxena P.R.
        • Zijlstra F.J.
        Time dependent production of cytokines and eicosanoids by human monocytic leukaemia U937 cells; effects of glucocorticosteroids.
        Mediators Inflamm. 1999; 8: 229-235
        • Molina-Holgado E.
        • Ortiz S.
        • Molina-Holgado F.
        • Guaza C.
        Induction of COX-2 and PGE(2) biosynthesis by IL-1beta is mediated by PKC and mitogen-activated protein kinases in murine astrocytes.
        Br J Pharmacol. 2000; 131: 152-159
        • Fan X.M.
        • Wong B.C.
        • Lin M.C.
        • Cho C.H.
        • Wang W.P.
        • Kung H.F.
        • et al.
        Interleukin-1beta induces cyclo-oxygenase-2 expression in gastric cancer cells by the p38 and p44/42 mitogen-activated protein kinase signaling pathways.
        J Gastroenterol Hepatol. 2001; 16: 1098-1104
        • Chen P.
        • Cai Y.
        • Yang Z.G.
        • Zhou R.
        • Zhang G.S.
        • Domann F.
        • et al.
        Involvement of PKC, p38 MAPK and AP-2 in IL-1beta-induced expression of cyclooxygenase-2 in human pulmonary epithelial cells.
        Respirology. 2006; 11: 18-23
        • Chen K.H.
        • Weng M.S.
        • Lin J.K.
        Tangeretin suppresses IL-1beta-induced cyclooxygenase (COX)-2 expression through inhibition of p38 MAPK, JNK, and AKT activation in human lung carcinoma cells.
        Biochem Pharmacol. 2007; 73: 215-227
        • MacGillivray M.K.
        • Cruz T.F.
        • McCulloch C.A.
        The recruitment of the interleukin-1 (IL-1) receptor-associated kinase (IRAK) into focal adhesion complexes is required for IL-1beta -induced ERK activation.
        J Biol Chem. 2000; 275: 23509-23515