Advertisement

Molecular and Cellular Biochemistry

, Volume 304, Issue 1–2, pp 71–77 | Cite as

Involvement of PPAR-γ and p53 in DHA-induced apoptosis in Reh cells

  • Hamid ZandEmail author
  • Ali Rhimipour
  • Masoomeh Bakhshayesh
  • Mohammad Shafiee
  • Issa Nour Mohammadi
  • Saideh Salimi
Article

Abstract

Docosahexaenoeic acid (DHA, 22:6 n-3) is an omega-3 polyunsaturated fatty acid that is found in fish oil and exerts cytotoxic effect on a variety of cell lines. The molecular target, responsible for mediating this effect of DHA, still remains unknown. In this report, we presented experimental evidences for the role of PPAR-γ in conveying the cytotoxic effect of DHA. We showed that DHA induces apoptosis in Reh and Ramos cells and apoptotic effect of DHA is inhibited by the PPAR-γ antagonist GW9662, indicating that PPAR-γ functions as the mediator of the apoptotic effect of DHA. Furthermore, our result showed that DHA induces the PPAR-γ protein levels in both Reh and Ramos cells. Interestingly, DHA was found to induce the expression of p53 protein in Reh cells in a PPAR-γ-dependent manner. The up-regulation of p53 protein by DHA kinetically correlated with the activation of caspase 9, caspase 3, and induction of apoptosis, suggesting a role for p53 in DHA-mediated apoptosis in Reh cells. Taken together, these findings suggest a new signaling pathway, DHA-PPAR-γ-p53, in mediating the apoptotic effect of DHA in Reh cells.

Keywords

DHA Polyunsaturated fatty acids PPAR- γ Apoptosis p53 

Notes

Acknowledgments

We are grateful to Professor Heidi Keil Blomhoff, Department of Biochemistry, Institute Group of Basic Medical Sciences, University of Oslo-Norway for allowing us to carry out most of this work in her laboratory. We also thank Dr Biserka Relic, Department of Rheumatology, University of Liege, Belgium for providing the PPAR-γ antibody.

References

  1. 1.
    Blot WJ, Lanier A, Fraumeni JR et al (1975) Cancer mortality among Alaskan natives. J Natl Cancer Inst 55:547–554PubMedGoogle Scholar
  2. 2.
    Nielsen NH, Hansen JP (1980) Breast cancer in Greenland-selected epidemiological, clinical, and histological features. J Cancer Res Clin Oncol 98:287–299PubMedCrossRefGoogle Scholar
  3. 3.
    Reddy BS, Burill C, Rigotty J (1991) Effect of diets high in omega-3 and omega-6 fatty acids on initiation and postinitiation stages of colon carcinogenesis. Cancer Res 1551:487–491Google Scholar
  4. 4.
    Hudson EA, Tisdale MJ (1994) Comparison of the effectiveness of eicosapentaenoic acid administered as either the free acid or ethyl ester as an anticachectic and antitumour agent. Prostaglandins Leukot Essent Fatty Acids 51:141–145PubMedCrossRefGoogle Scholar
  5. 5.
    Begin ME, Ells G, Das UN, Horrobin DF (1986) Differential killing of human carcinoma cells supplemented with n-3 and n-6 polyunsaturated fatty acids. J Natl Cancer Inst 77:1053–1062PubMedGoogle Scholar
  6. 6.
    Calviello G, Palozza P, Piccioni E et al (1998) Dietary supplementation with eicosapentaenoic and docosahexaenoic acid inhibits growth of Morris hepatocarcinoma 3924A in rats effects on proliferation and apoptosis. Int J Cancer 275:699–705CrossRefGoogle Scholar
  7. 7.
    Siddiqui RA, Jenski LJ, Harvey KA et al (2003) Cell-cycle arrest in Jurkat leukaemic cells a possible role for docosahexaenoic acid. Biochem J 5371:621–629CrossRefGoogle Scholar
  8. 8.
    Finstad HS, Dyrendal H, Myhrstad MC et al (2000) Uptake and activation of eicosapentaenoic acid are related to accumulation of triacylglycerol in Ramos cells dying from apoptosis. J Lipid Res 41:554–563PubMedGoogle Scholar
  9. 9.
    Ding WQ, Vaught JL, Yamauchi H et al (2004) Differential sensitivity of cancer cells to docosahexaenoic acid-induced cytotoxicity the potential importance of down-regulation of superoxide dismutase 1 expression. Mol Cancer Ther 3:1109–1117PubMedCrossRefGoogle Scholar
  10. 10.
    Obata T, Nagakura T, Masaki T et al (1991) Eicosapentaenoic acid inhibits prostaglandin D2 generation by inhibiting cyclo-oxygenase-2 in cultured human mast cells. Clin Exp Allergy 29:1129–1135CrossRefGoogle Scholar
  11. 11.
    Hamid R, Singh J, Reddy RS et al (1999) Inhibition by dietary menhaden oil of cyclooxygenase-1 and -2 in N-nitrosomethylurea-induced rat mammary tumors. Int J Oncol 14:523–528PubMedGoogle Scholar
  12. 12.
    Chamras H, Ardashian A, Heber D et al (2002) Fatty acid modulation of MCF-7 human breast cancer cell proliferation, apoptosis and differentiation. J Nutr Biochem 13:711–716PubMedCrossRefGoogle Scholar
  13. 13.
    Narayanan BA, Narayanan NK, Reddy BS et al (2001) Docosahexaenoic acid regulated genes and transcription factors inducing apoptosis in human colon cancer cells. Int J Oncol 19:1255–1262PubMedGoogle Scholar
  14. 14.
    Chiu LC, Wong EY, Ooi VE (2004) Docosahexaenoic acid from a cultured microalga inhibits cell growth and induces apoptosis by upregulating Bax/Bcl-2 ratio in human breast carcinoma MCF-7 cells. Ann N Y Acad Sci 25:734–744Google Scholar
  15. 15.
    Denys A, Hichami A, Akhan N (2005) n-3 PUFAs modulate T-cell activation via protein kinase C-alpha and -epsilon and the NF-kappaB signaling pathway. J Lipid Res 46:752–758PubMedCrossRefGoogle Scholar
  16. 16.
    Zhao G, Etherton TD, Martin KR et al (2006) Anti-inflammatory effects of polyunsaturated fatty acids in THP-1 cells. Biochem Biophys Res Commun 336:909–917CrossRefGoogle Scholar
  17. 17.
    Schoonjans K, Staels B, Auwerx J (1996) The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 26130:93–109Google Scholar
  18. 18.
    Boitier E, Gautier JC, Roberts R (2003) Advances in understanding the regulation of apoptosis and mitosis by peroxisome-proliferator activated receptors in pre-clinical models relevance for human health and disease. Comp Hepatol 312: 3CrossRefGoogle Scholar
  19. 19.
    Chawla A, Repa JJ, Evans RM et al (2001) Nuclear receptors and lipid physiology opening the X-files. Science 30294:1866–1870CrossRefGoogle Scholar
  20. 20.
    Padilla J, Kaur K, Cao HJ et al (2000) Peroxisome proliferator activator receptor-gamma agonists and 15-deoxy-Delta(12,14)(12,14)-PGJ(2) induce apoptosis in normal and malignant B-lineage cells. J Immunol 15165:6941–6948Google Scholar
  21. 21.
    Wakino S, Kintscher U, Liu Z et al (2001) Peroxisome proliferator-activated receptor gamma ligands inhibit mitogenic induction of p21(Cip1) by modulating the protein kinase C delta pathway in vascular smooth muscle cells. J Biol Chem 276:47650–47657PubMedCrossRefGoogle Scholar
  22. 22.
    Fan YY, Spencer TE, Wang N et al (2003) Chemopreventive n-3 fatty acids activate RXR alpha in colonocytes. Carcinogenesis 24:1541–1548PubMedCrossRefGoogle Scholar
  23. 23.
    Fujimura S, Suzumiya J, Nakamura K et al (1998) Effects of troglitazone on the growth and differentiation of hematopoietic cell lines. Int J Oncol 13:1263–1267PubMedGoogle Scholar
  24. 24.
    Konopleva M, Andreeff M (2002) Role of peroxisome proliferator-activated receptor-gamma in hematologic malignancies. Curr Opin Hematol 9:294–302PubMedCrossRefGoogle Scholar
  25. 25.
    Padilla J, Leung E, Phipps R.P (2002) Human B lymphocytes and B lymphomas express PPAR-gamma and are killed by PPAR-gamma agonists. Clin Immunol 103:22–33PubMedCrossRefGoogle Scholar
  26. 26.
    Rosen A, Casciola-Rosen L (1997) Macromolecular substrates for the ICE-like proteases during apoptosis. J Cell Biochem 64:50–54PubMedCrossRefGoogle Scholar
  27. 27.
    Anel A, Naval J, Desportes P et al (1992) Increased cytotoxicity of polyunsaturated fatty acids on human tumoral B and T-cell lines compared with normal lymphocytes. Leukemia 6:680–688PubMedGoogle Scholar
  28. 28.
    Heimli H, Giske C, Naderi S et al (2002) Eicosapentaenoic acid promotes apoptosis in Ramos cells via activation of caspase-3 and -9. Lipids 37:797–802PubMedCrossRefGoogle Scholar
  29. 29.
    Finstad HS, Myhrstad MC, Heimli H et al (1998) Multiplication and death-type of leukemia cell lines exposed to very long-chain polyunsaturated fatty acids. Leukemia 12:921–929PubMedCrossRefGoogle Scholar
  30. 30.
    Leesnitzer LM, Parks DJ, Bledsoe RK et al (2002) Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry 41:6640–6650PubMedCrossRefGoogle Scholar
  31. 31.
    Yu C, Chen L, Luo H et al (2004) Binding analyses between Human PPARgamma-LBD and ligands. Eur J Biochem 271:386–397PubMedCrossRefGoogle Scholar
  32. 32.
    Lee H, Finck BN, Jones LA et al(2006) Synthesis and evaluation of a bromine-76-labeled PPARgamma antagonist 2-bromo-5-nitro-N-phenylbenzamide. Nucl Med Biol 33:847–854PubMedCrossRefGoogle Scholar
  33. 33.
    Hampel JK, Brownrigg LM, Vignarajah D et al (2006) Differential modulation of cell cycle, apoptosis and PPARgamma2 gene expression by PPARgamma agonists ciglitazone and 9-hydroxyoctadecadienoic acid in monocytic cells. Prostaglandins Leukot Essent Fatty Acids 74:283–293PubMedCrossRefGoogle Scholar
  34. 34.
    Lorente-Cebrian S, Perez-Matute P, Martinez JA et al (2006) Effects of eicosapentaenoic acid (EPA) on adiponectin gene expression and secretion in primary cultured rat adipocytes. J Physiol Biochem 62:61–69PubMedCrossRefGoogle Scholar
  35. 35.
    Tsujita-Kyutoku M, Yuri T, Danbara N et al (2004) Conjugated docosahexaenoic acid suppresses KPL-1 human breast cancer cell growth in vitro and in vivo: potential mechanisms of action. Breast Cancer Res 6: R291–R299PubMedCrossRefGoogle Scholar
  36. 36.
    Narayanan NK, Narayanan BA, Bosland M et al (2006) Docosahexaenoic acid in combination with celecoxib modulates HSP70 and p53 proteins in prostate cancer cells. Int J Cancer 119:1586–1598PubMedCrossRefGoogle Scholar
  37. 37.
    Li M, Lee TW, Yim AP et al (2006) Apoptosis induced by troglitazone is both peroxisome proliferator-activated receptor-gamma- and ERK-dependent in human non-small lung cancer cells. J Cell Physiol 209:428–438PubMedCrossRefGoogle Scholar
  38. 38.
    Lovekamp-Swan T, Chaffin CL (2005) The peroxisome proliferator-activated receptor gamma ligand troglitazone induces apoptosis and p53 in rat granulosa cells. Mol Cell Endocrinol 233:15–24PubMedCrossRefGoogle Scholar
  39. 39.
    Chipuk JE, Green DR (2006) Dissecting p53-dependent apoptosis. Cell Death Differ 13:994–1002PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Hamid Zand
    • 1
    Email author
  • Ali Rhimipour
    • 1
  • Masoomeh Bakhshayesh
    • 2
  • Mohammad Shafiee
    • 2
  • Issa Nour Mohammadi
    • 2
  • Saideh Salimi
    • 2
  1. 1.Faculty of Medicine, Department of BiochemistryTabriz Medical Sciences UniversityTabrizIran
  2. 2.Cellular and Molecular Biology Research CenterIran University Medical SciencesTehranIran

Personalised recommendations