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Cyclo-oxygenase-Independent Inhibition of Apoptosis and Stimulation of Proliferation by Leptin in Human Colon Cancer Cells

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Abstract

Obesity increases the risk of colon cancer. Hyperleptinemia is characteristic of obesity and leptin has been reported to be a colonic growth factor. We have examined the involvement of the cyclo-oxygenase (COX) pathways in the proliferation and anti-apoptotic effects of leptin. Leptin stimulated proliferation in HT-29 colon cancer cells: this was unaffected by inhibition of COX-1, COX-2, protein kinase C, or the epidermal growth factor receptor. Leptin did not increase COX-2 mRNA or COX-derived prostaglandin E2 production. Celecoxib induced apoptosis in a COX-independent manner. Leptin reduced both serum starvation- and celecoxib-induced apoptosis. Inhibition of ERK, p38 MAP kinase, and nuclear factor (NF)-κB abolished the growth-promoting and anti-apoptotic effects of leptin. Treatment of HT-29 cells with leptin stimulated phosphorylation of ERK and p38 MAP kinase and nuclear translocation of active NF-κB. We conclude that leptin stimulates colon cancer proliferation via COX-independent pathways and reduces celecoxib-induced apoptosis via ERK, p38 MAP kinase, and NF-κB pathways.

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References

  1. Baratta M (2002) Leptin—from a signal of adiposity to a hormonal mediator in peripheral tissues. Med Sci Monit 8:RA282–RA292

    PubMed  CAS  Google Scholar 

  2. Somasundar P, Yu AK, Vona-Davis L, McFadden DW (2003) Differential effects of leptin on cancer in vitro. J Surg Res 113:50–55

    Article  PubMed  CAS  Google Scholar 

  3. Attoub S, Noe V, Pirola L, Bruyneel E, Chastre E, Mareel M, Wymann MP, Gespach C (2000) Leptin promotes invasiveness of kidney and colonic epithelial cells via phosphoinositide 3-kinase-, rho-, and rac-dependent signaling pathways. FASEB J 14:2329–2338

    Article  PubMed  CAS  Google Scholar 

  4. Hardwick JC, Van Den Brink GR, Offerhaus GJ, van Deventer SJ, Peppelenbosch MP (2001) Leptin is a growth factor for colonic epithelial cells. Gastroenterology 121:79–90

    Article  PubMed  CAS  Google Scholar 

  5. Hegyi K, Fulop K, Kovacs K, Toth S, Falus A (2004) Leptin-induced signal transduction pathways. Cell Biol Int 28:159–169

    Article  PubMed  CAS  Google Scholar 

  6. Dal Farra C, Zsurger N, Vincent JP, Cupo A (2000) Binding of a pure 125I-monoiodoleptin analog to mouse tissues: a developmental study. Peptides 21:577–587

    Article  PubMed  CAS  Google Scholar 

  7. Giovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, Willett WC (1995) Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann Intern Med 122:327–324

    PubMed  CAS  Google Scholar 

  8. Pan SY, Johnson KC, Ugnat AM, Wen SW, Mao Y (2004) Association of obesity and cancer risk in Canada. Am J Epidemiol 159:259–268

    Article  PubMed  Google Scholar 

  9. Stattin P, Lukanova A, Biessy C, Soderberg S, Palmqvist R, Kaaks R, Olsson T, Jellum E (2004) Obesity and colon cancer: Does leptin provide a link? Int J Cancer 109:149–152

    Article  PubMed  CAS  Google Scholar 

  10. Yao M, Lam EC, Kelly CR, Zhou W, Wolfe MM (2004) Cyclooxygenase-2 selective inhibition with NS-398 suppresses proliferation and invasiveness and delays liver metastasis in colorectal cancer. Br J Cancer 90:712–719

    Article  PubMed  CAS  Google Scholar 

  11. Mann JR, Dubois RN (2004) Cyclooxygenase-2 and gastrointestinal cancer. Cancer J 10:145–152

    Article  PubMed  CAS  Google Scholar 

  12. Kismet K, Akay MT, Abbasoglu O, Ercan A (2004) Celecoxib: a potent cyclooxygenase-2 inhibitor in cancer prevention. Cancer Detect Prev 28:127–142

    Article  PubMed  CAS  Google Scholar 

  13. Tuynman JB, Peppelenbosch MP, Richel DJ (2004) COX-2 inhibition as a tool to treat and prevent colorectal cancer. Crit Rev Oncol Hematol 52:81–101

    PubMed  CAS  Google Scholar 

  14. Yao M, Song DH, Rana B, Wolfe MM (2002) COX-2 selective inhibition reverses the trophic properties of gastrin in colorectal cancer. Br J Cancer 87:574–579

    Article  PubMed  CAS  Google Scholar 

  15. Luo JC, Shin VY, Yang YH, Wu WK, Ye YN, So WH, Chang FY, Cho CH (2005) Tumor necrosis factor-α stimulates gastric epithelial cell proliferation. Am J Physiol Gastrointest Liver Physiol 288:G32–G38

    Article  PubMed  CAS  Google Scholar 

  16. Souza RF, Shewmake K, Pearson S, Sarosi GA Jr, Feagins LA, Ramirez RD, Terada LS, Spechler SJ (2004) Acid increases proliferation via ERK and p38 MAPK-mediated increases in cyclooxygenase-2 in Barrett’s adenocarcinoma cells. Am J Physiol Gastrointest Liver Physiol 287:G743–G748

    Article  PubMed  CAS  Google Scholar 

  17. Hawcroft G, Ko CW, Hull MA (2006) Prostaglandin E(2)-EP4 receptor signalling promotes tumorigenic behaviour of HT-29 human colorectal cancer cells. Oncogene (epub ahead of print, 20 Nov 2006 doi, 10.10138/sj.onc.1210113)

  18. Yamazaki R, Kusunoki N, Matsuzaki T, Hashimoto S, Kawai S (2002) Selective cyclooxygenase-2 inhibitors show a differential ability to inhibit proliferation and induce apoptosis of colon adenocarcinoma cells. FEBS Lett 531:278–284

    Article  PubMed  CAS  Google Scholar 

  19. Grosch S, Tegeder I, Niederberger E, Brautigam L, Geisslinger G (2001) COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. FASEB J 15:2742–2744

    PubMed  CAS  Google Scholar 

  20. Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, Bertagnolli M (2005) Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352:1071–1080

    Article  PubMed  CAS  Google Scholar 

  21. Saxena NK, Titus MA, Ding X, Floyd J, Srinivasan S, Sitaraman SV, Anania FA (2004) Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation. FASEB J 18:1612–1614

    PubMed  CAS  Google Scholar 

  22. van den Brink GR, O’Toole T, Hardwick JC, van den Boogaardt DE, Versteeg HH, van Deventer SJ, Peppelenbosch MP (2000) Leptin signaling in human peripheral blood mononuclear cells, activation of p38 and p42/44 mitogen-activated protein (MAP) kinase and p70 S6 kinase. Mol Cell Biol Res Commun 4:144–150

    Article  PubMed  CAS  Google Scholar 

  23. Bjorbaek C, Buchholz RM, Davis SM, Bates SH, Pierroz DD, Gu H, Neel BG, Myers MG Jr, Flier JS (2001) Divergent roles of SHP-2 in ERK activation by leptin receptors. J Biol Chem 276:4747–4755

    Article  PubMed  CAS  Google Scholar 

  24. Dreyer MG, Juge-Aubry CE, Gabay C, Lang U, Rohner-Jeanrenaud F, Dayer JM, Meier CA (2003) Leptin activates the promoter of the interleukin-1 receptor antagonist through p42/44 mitogen-activated protein kinase and a composite nuclear factor kappa B/PU.1 binding site. Biochem J 370:591–599

    Article  PubMed  CAS  Google Scholar 

  25. Kim GS, Hong JS, Kim SW, Koh JM, An CS, Choi JY, Cheng SL (2003) Leptin induces apoptosis via ERK/cPLA2/cytochrome c pathway in human bone marrow stromal cells. J Biol Chem 278:21920–21929

    Article  PubMed  CAS  Google Scholar 

  26. Maroni P, Bendinelli P, Piccoletti R (2003) Early intracellular events induced by in vivo leptin treatment in mouse skeletal muscle. Mol Cell Endocrinol 201:109–121

    Article  PubMed  CAS  Google Scholar 

  27. Thamilselvan V, Li W, Sumpio BE, Basson MD (2002) Sphingosine-1-phosphate stimulates human Caco-2 intestinal epithelial proliferation via p38 activation and activates ERK by an independent mechanism. In Vitro Cell Dev Biol Anim 38:246–253

    Article  PubMed  CAS  Google Scholar 

  28. Rouet-Benzineb P, Aparicio T, Guilmeau S, Pouzet C, Descatoire V, Buyse M, Bado A (2004) Leptin counteracts sodium butyrate-induced apoptosis in human colon cancer HT-29 cells via NF-kappaB signaling. J Biol Chem 279:16495–16502

    Article  PubMed  CAS  Google Scholar 

  29. Colucci R, Blandizzi C, Tanini M, Vassalle C, Breschi MC, Tacca MD (2005) Gastrin promotes human colon cancer cell growth via CCK-2 receptor-mediated cyclooxygenase-2 induction and prostaglandin E(2) production. Br J Pharmacol 144:338–348

    Article  PubMed  CAS  Google Scholar 

  30. Todisco A, Ramamoorthy S, Witham T, Pausawasdi N, Srinivasan S, Dickinson CJ, Askari FK, Krametter D (2001) Molecular mechanisms for the antiapoptotic action of gastrin. Am J Physiol Gastrointest Liver Physiol 280:G298–G307

    PubMed  CAS  Google Scholar 

  31. Ogunwobi OO, Beales ILP (2006) Adiponectin stimulates proliferation and cytokine secretion in colonic epithelial cells. Regul Peptides 134:105–113

    Article  CAS  Google Scholar 

  32. Ogunwobi O, Mutungi G, Beales IL (2006) Leptin stimulates proliferation and inhibits apoptosis in Barrett’s esophageal adenocarcinoma cells by cyclooxygenase-2-dependent, prostaglandin-E2-mediated transactivation of the epidermal growth factor receptor and c-Jun NH2-terminal kinase activation. Endocrinology 147:4505–4516

    Article  PubMed  CAS  Google Scholar 

  33. Beales IL, Ogunwobi O (2006) Glycine-extended gastrin inhibits apoptosis in colon cancer cells via separate activation of Akt and JNK pathways. Mol Cell Endocrinol 247:140–149

    Article  PubMed  CAS  Google Scholar 

  34. Cory AH, Owen TC, Barltrop JA, Cory JG (1991) Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Commun 3:207–212

    PubMed  CAS  Google Scholar 

  35. Beales IL (2004) Gastrin and interleukin-1beta stimulate growth factor secretion from cultured rabbit gastric parietal cells. Life Sci 75:2983–2995

    Article  PubMed  CAS  Google Scholar 

  36. Ogunwobi OO, Beales IL (2006) Glycine-extended gastrin stimulates proliferation and inhibits apoptosis in colon cancer cells via cyclo-oxygenase-independent pathways. Regul Pept 134:1–8

    Article  PubMed  CAS  Google Scholar 

  37. Souza RF, Shewmake K, Beer DG, Cryer B, Spechler SJ (2000) Selective inhibition of cyclooxygenase-2 suppresses growth and induces apoptosis in human esophageal adenocarcinoma cells. Cancer Res 60:5767–5772

    PubMed  CAS  Google Scholar 

  38. Ropeleski MJ, Riehm J, Baer KA, Musch MW, Chang EB (2005) Anti-apoptotic effects of L-glutamine-mediated transcriptional modulation of the heat shock protein 72 during heat shock. Gastroenterology 129:170–184

    Article  PubMed  CAS  Google Scholar 

  39. Hsi LC, Baek SJ, Eling TE (2000) Lack of cyclooxygenase-2 activity in HT-29 human colorectal carcinoma cells. Exp Cell Res 256:563–570

    Article  PubMed  CAS  Google Scholar 

  40. Sharma RA, Gescher A, Plastaras JP, Leuratti C, Singh R, Gallacher-Horley B, Offord E, Marnett LJ, Steward WP, Plummer SM (2001) Cyclooxygenase-2, malondialdehyde and pyrimidopurinone adducts of deoxyguanosine in human colon cells. Carcinogenesis 22:1557–1560

    Article  PubMed  CAS  Google Scholar 

  41. Yang WL, Frucht H (2000) Cholinergic receptor up-regulates COX-2 expression and prostaglandin E(2) production in colon cancer cells. Carcinogenesis 21:1789–1793

    Article  PubMed  CAS  Google Scholar 

  42. Fujiwara Y, Higuchi K, Tominaga K, Watanabe T, Oshitani N, Arakawa T (2005) Functional oesophageal epithelial defense against acid. Inflammopharmacology 13:1–13

    Article  PubMed  CAS  Google Scholar 

  43. Ukegawa JI, Takeuchi Y, Kusayanagi S, Mitamura K (2003) Growth-promoting effect of muscarinic acetylcholine receptors in colon cancer cells. J Cancer Res Clin Oncol 129:272–278

    PubMed  CAS  Google Scholar 

  44. Pai R, Soreghan B, Szabo IL, Pavelka M, Baatar D, Tarnawski AS (2002) Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med 8:289–293

    Article  PubMed  CAS  Google Scholar 

  45. Choy H, Milas L (2003) Enhancing radiotherapy with cyclooxygenase-2 enzyme inhibitors: A rational advance? J Natl Cancer Inst 95:1440–1452

    PubMed  CAS  Google Scholar 

  46. Sun Y, Sinicrope FA (2005) Selective inhibitors of MEK1/ERK44/42 and p38 mitogen-activated protein kinases potentiate apoptosis induction by sulindac sulfide in human colon carcinoma cells. Mol Cancer Ther 4:51–59

    PubMed  CAS  Google Scholar 

  47. Nishihara H, Hwang M, Kizaka-Kondoh S, Eckmann L, Insel PA (2004) Cyclic AMP promotes cAMP-responsive element-binding protein-dependent induction of cellular inhibitor of apoptosis protein-2 and suppresses apoptosis of colon cancer cells through ERK1/2 and p38 MAPK. J Biol Chem 279:26176–26183

    Article  PubMed  CAS  Google Scholar 

  48. Chan UP, Lee JF, Wang SH, Leung KL, Chen GG (2003) Induction of colon cancer cell death by 7-hydroxystaurosporine (UCN-01) is associated with increased p38 MAPK and decreased Bcl-xL. Anticancer Drugs 14:761–766

    Article  PubMed  CAS  Google Scholar 

  49. Lee EJ, Park HG, Kang HS (2003) Sodium salicylate induces apoptosis in HCT116 colorectal cancer cells through activation of p38MAPK. Int J Oncol 23:503–508

    PubMed  CAS  Google Scholar 

  50. Wang CY, Mayo MW, Baldwin AS Jr (1996) TNF- and cancer therapy-induced apoptosis: potentiation by inhibition ofNF-kappaB. Science 274:784–787

    Article  PubMed  CAS  Google Scholar 

  51. Ghosh S, May MJ, Kopp EB (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260

    Article  PubMed  CAS  Google Scholar 

  52. Reuther-Madrid JY, Kashatus D, Chen S, Li X, Westwick J, Davis RJ, Earp HS, Wang CY, Baldwin AS Jr (2002) The p65/RelA subunit of NF-kappaB suppresses the sustained, antiapoptotic activity of Jun kinase induced by tumor necrosis factor. Mol Cell Biol 22:8175–8183

    Article  PubMed  CAS  Google Scholar 

  53. Garrouste F, Remacle-Bonnet M, Fauriat C, Marvaldi J, Luis J, Pommier G (2002) Prevention of cytokine-induced apoptosis by insulin-like growth factor-I is independent of cell adhesion molecules in HT29-D4 colon carcinoma cells-evidence for a NF-kappaB-dependent survival mechanism. Cell Death Differ 9:768–769

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was funded by the Norfolk andNorwich University Hospital Bicentenary Trust in the form of a Research Studentship to Dr. Ogunwobi. Further financial support was provided by The Royal Society, The Peel Medical Research Trust, The Mason Medical Research Foundation, The Institute of Biomedical Science, NHS Research and Development Funding, and the Norfolk and Norwich University Hospital Inflammatory Bowel Disease Research Fund.

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Authors and Affiliations

  1. Gastroenterology Research Unit, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, NR4 7TJ, UK

    Olorunseun Olatunji Ogunwobi & Ian L. P. Beales

  2. Gastroenterology Department, Norfolk and Norwich University Hospital, NR4 7UZ, Norwich, UK

    Ian L. P. Beales

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  1. Olorunseun Olatunji Ogunwobi
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  2. Ian L. P. Beales
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Correspondence to Ian L. P. Beales.

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Ogunwobi, O.O., Beales, I.L.P. Cyclo-oxygenase-Independent Inhibition of Apoptosis and Stimulation of Proliferation by Leptin in Human Colon Cancer Cells. Dig Dis Sci 52, 1934–1945 (2007). https://doi.org/10.1007/s10620-007-9784-6

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  • DOI: https://doi.org/10.1007/s10620-007-9784-6

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