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Ligands for PPARγ and RAR Cause Induction of Growth Inhibition and Apoptosis in Human Glioblastomas

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Abstract

High-grade gliomas are characterized by a rapid proliferation rate, invasiveness and angiogenesis. Our previous data indicated that the combination of ligands for peroxisome proliferator-activated receptor γ (PPARγ) and retinoic acid receptor (RAR) induces apoptosis of breast cancer cells in vitro and in a murine model. In this study, we have shown that 11 glioblastoma cell lines and nine fresh glioblastoma tissue samples from patients expressed high-levels of PPARγ. In contrast, glia from nine healthy human brains expressed very low levels of PPARγ. No mutations or polymorphisms of the PPARγ gene were observed in these cell lines. The effect of the PPARγ ligand Pioglitazone (PGZ) either in the absence or in the presence of a RAR ligand [all-trans retinoic acid (ATRA)] on the proliferation and apoptosis of glioblastoma cells was examined using two glioblastoma cell lines (N39 and DBTRG05MG). PGZ and/or ATRA inhibited significantly the proliferation of both cell lines. Flow cytometry analysis showed that G1 cell cycle arrest was induced by these ligands. In addition, apoptosis occurred in both cell lines treated with either PGZ or ATRA, which was associated with a downregulation of bcl-2 and an upregulation of bax proteins. An enhanced effect was observed when PGZ and ATRA were combined. Furthermore, treatment of fresh glioblastoma tissue from patients with PGZ, either alone or in combination with ATRA, induced a significant level of tumor cell apoptosis together with a downregulation of bcl-2 protein level as compared with untreated control brain tissue. Taken together, our data demonstrated that PGZ, either alone or in combination with ATRA, induced apoptosis and inhibited proliferation of glioblastoma cells, and more interestingly, induced apoptosis of fresh glioblastoma cells from patients. Therefore, we conclude that these ligands may possess adjuvant therapeutic potential for patients with glioblastoma.

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References

  1. Levin VA: Chemotherapy for brain tumors of astrocytic and oligodendroglial lineage: the past decade and where we are heading. Neuro-Oncology 1: 69–80, 1999

    Google Scholar 

  2. Hildebrand J, Dewitte O, Dietrich PY, de Tribolet N: Management of malignant brain tumors. Eur Neurol 38: 238–253, 1997

    Google Scholar 

  3. Shrieve DC, Alexander III, E, Black PM, Wen PY, Fine HA, Kooy HM, Loeffler JS: Treatment of patients with primary glioblastoma multiforme with standard postoperative radiotherapy and radiosurgical boost: prognostic factors and long-term outcome. J Neurosurg 90: 72–77, 1999

    Google Scholar 

  4. Chawla A, Schwarz EJ, Dimaculangan DD, Lazar MA: Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology 135: 798–800, 1994

    Google Scholar 

  5. Tontonoz P, Graves RA, Budavari AI, Erdjument-Bromage H, Lui M, Hu E, Tempst P, Spiegelman BM: Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR gamma and RXR alpha. Nucleic Acids Res 22: 5628–5634, 1994

    Google Scholar 

  6. Brun RP, Kim JB, Hu E, Spiegelman BM: Peroxisome proliferator-activated receptor gamma and the control of adipogenesis. Curr Opin Lipidol 8: 212–218, 1997

    Google Scholar 

  7. Spiegelman BM: PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 47: 507–514, 1998

    Google Scholar 

  8. Delerive P, Fruchart JC, Staels B: Peroxisome proliferatoractivated receptors in inflammation control. J Endocrinol 169: 453–459, 2001

    Google Scholar 

  9. Gelman L, Fruchart JC, Auwerx J: An update on the mechanisms of action of the peroxisome proliferator-activated receptors (PPARs) and their roles in inflammation and cancer. Cell Mol Life Sci 55: 932–943, 1999

    Google Scholar 

  10. Roberts-Thomson SJ: Peroxisome proliferator-activated receptors in tumorigenesis: targets of tumour promotion and treatment. Immunol Cell Biol 78: 436–441, 2000

    Google Scholar 

  11. Girnun GD, Smith WM, Drori S, Sarraf P, Mueller E, Eng C, Nambiar P, Rosenberg DW, Bronson RT, Edelmann W, Kucherlapati R, Gonzalez FJ, Spiegelman BM: APCdependent suppression of colon carcinogenesis by PPARgamma. Proc Natl Acad Sci USA 99: 13771–13776, 2002

    Google Scholar 

  12. Tontonoz P, Singer S, Forman BM, Sarraf P, Fletcher JA, Fletcher CD, Brun RP, Mueller E, Altiok S, Oppenheim H, Evans RM, Spiegelman BM: Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Proc Natl Acad Sci USA 94: 237–241, 1997

    Google Scholar 

  13. Demetri GD, Fletcher CD, Mueller E, Sarraf P, Naujoks R, Campbell N, Spiegelman BM, Singer S: Induction of solid tumor differentiation by the peroxisome proliferatoractivated receptor-gamma ligand troglitazone in patients with liposarcoma. Proc Natl Acad Sci USA 96: 3951–3956, 1999

    Google Scholar 

  14. Kubota T, Koshizuka K, Williamson EA, Asou H, Said JW, Holden S, Miyoshi I, Koeffler HP: Ligand for peroxisome proliferator-activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res 58: 3344–3352, 1998

    Google Scholar 

  15. Mueller E, Smith M, Sarraf P, Kroll T, Aiyer A, Kaufman DS, Oh W, Demetri G, Figg WD, Zhou XP, Eng C, Spiegelman BM, Kantoff PW: Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proc Natl Acad Sci USA 97: 10990–10995, 2000

    Google Scholar 

  16. Brockman JA, Gupta RA, Dubois RN: Activation of PPARgamma leads to inhibition of anchorage-independent growth of human colorectal cancer cells. Gastroenterology 115: 1049–1055, 1998

    Google Scholar 

  17. Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Partridge JB, Holden SA, Chen LB, Singer S, Fletcher C, Spiegelman BM: Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat Med 4: 1046–1052, 1998

    Google Scholar 

  18. Kitamura S, Miyazaki Y, Shinomura Y, Kondo S, Kanayama S, Matsuzawa Y: Peroxisome proliferatoractivated receptor gamma induces growth arrest and differentiation markers of human colon cancer cells. Jpn J Cancer Res 90: 75–80, 1999

    Google Scholar 

  19. Yang WL, Frucht H: Activation of the PPAR pathway induces apoptosis and COX-2 inhibition in HT-29 human colon cancer cells. Carcinogenesis 22: 1379–1383, 2001

    Google Scholar 

  20. Elstner E, Mueller C, Koshizuka K, Williamson EA, Park D, Asou H, Shintaku P, Said JW, Heber D, Koeffler HP: Ligands for peroxisome proliferator-activated receptor gamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci USA 95: 8806–8811, 1998

    Google Scholar 

  21. Kilgore MW, Tate PL, Rai S, Sengoku E, Price TM: MCF-7 and T47D human breast cancer cells contain a functional peroxisomal response. Mol Cell Endocrinol 129: 229–235, 1997

    Google Scholar 

  22. Mueller E, Sarraf P, Tontonoz P, Evans RM, Martin KJ, Zhang M, Fletcher C, Singer S, Spiegelman BM: Terminal differentiation of human breast cancer through PPAR gamma. Mol Cell 1: 465–470, 1998

    Google Scholar 

  23. Takahashi N, Okumura T, Motomura W, Fujimoto Y, Kawabata I, Kohgo Y: Activation of PPARgamma inhibits cell growth and induces apoptosis in human gastric cancer cells. FEBS Lett 455: 135–139, 1999

    Google Scholar 

  24. Sato H, Ishihara S, Kawashima K, Moriyama N, Suetsugu H, Kazumori H, Okuyama T, Rumi MA, Fukuda R, Nagasue N, Kinoshita Y: Expression of peroxisome proliferatoractivated receptor (PPAR)gamma in gastric cancer and inhibitory effects of PPARgamma agonists. Br J Cancer 83: 1394–1400, 2000

    Google Scholar 

  25. Chang TH, Szabo E: Induction of differentiation and apoptosis by ligands of peroxisome proliferator-activated receptor gamma in non-small cell lung cancer. Cancer Res 60: 1129–1138, 2000

    Google Scholar 

  26. Tsubouchi Y, Sano H, Kawahito Y, Mukai S, Yamada R, Kohno M, Inoue K, Hla T, Kondo M: Inhibition of human lung cancer cell growth by the peroxisome proliferatoractivated receptor-gamma agonists through induction of apoptosis. Biochem Biophys Res Commun 270: 400–405, 2000

    Google Scholar 

  27. Motomura W, Okumura T, Takahashi N, Obara T, Kohgo Y: Activation of peroxisome proliferator-activated receptor gamma by troglitazone inhibits cell growth through the increase of p27KiP1 in human pancreatic carcinoma cells. Cancer Res 60: 5558–5564, 2000

    Google Scholar 

  28. Elnemr A, Ohta T, Iwata K, Ninomia I, Fushida S, Nishimura GI, Kitagawa H, Kayahara M, Yamamoto M, Terada T, Miwa K: PPARgamma ligand (thiazolidinedione) induces growth arrest and differentiation markers of human pancreatic cancer cells. Int J Oncol 17: 1157–1164, 2000

    Google Scholar 

  29. Asou H, Verbeek W, Williamson E, Elstner E, Kubota T, Kamada N, Koeffler HP: Growth inhibition of myeloid leukemia cells by troglitazone, a ligand for peroxisome proliferator activated receptor gamma, and retinoids. Int J Oncol 15: 1027–1031, 1999

    Google Scholar 

  30. Berger J, Bailey P, Biswas C, Cullinan CA, Doebber TW, Hayes NS, Saperstein R, Smith RG, Leibowitz MD: Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology 137: 4189–4195, 1996

    Google Scholar 

  31. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA: An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferatoractivated receptor gamma (PPARgamma). J Biol Chem 270: 12953–12956, 1995

    Google Scholar 

  32. Lambe KG, Tugwood JD: A human peroxisomeproliferator-activated receptor-gamma is activated by inducers of adipogenesis, including thiazolidinedione drugs. Eur J Biochem 239: 1–7, 1996

    Google Scholar 

  33. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM: 15-Deoxy-delta 12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 83: 803–812, 1995

    Google Scholar 

  34. Elbrecht A, Chen Y, Cullinan CA, Hayes N, Leibowitz M, Moller DE, Berger J: Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors gamma 1 and gamma 2. Biochem Biophys Res Commun 224: 431–437, 1996

    Google Scholar 

  35. Nwankwo JO, Robbins ME: Peroxisome proliferatoractivated receptor-gamma expression in human malignant and normal brain, breast and prostate-derived cells. Prostaglandins Leukot Essent Fatty Acids 64: 241–245, 2001

    Google Scholar 

  36. Prasanna P, Thibault A, Liu L, Samid D: Lipid metabolism as a target for brain cancer therapy: synergistic activity of lovastatin and sodium phenylacetate against human glioma cells. J Neurochem 66: 710–716, 1996

    Google Scholar 

  37. Chattopadhyay N, Singh DP, Heese O, Godbole MM, Sinohara T, Black PM, Brown EM: Expression of peroxisome proliferator-activated receptors (PPARS) in human astrocytic cells: PPARgamma agonists as inducers of apoptosis. J Neurosci Res 61: 67–74, 2000

    Google Scholar 

  38. Zander T, Kraus JA, Grommes C, Schlegel U, Feinstein D, Klockgether T, Landreth G, Koenigsknecht J, Heneka MT: Induction of apoptosis in human and rat glioma by agonists of the nuclear receptor PPARgamma. J Neurochem 81: 1052–1060, 2002

    Google Scholar 

  39. Yung WK, Lotan R, Lee P, Lotan D, Steck PA: Modulation of growth and epidermal growth factor receptor activity by retinoic acid in human glioma cells. Cancer Res 49: 1014–1019, 1989

    Google Scholar 

  40. Higashida H, Miki N, Ito M, Iwata T, Tsukida K: Cytotoxic action of retinoidal butenolides on mouse neuroblastoma and rat glioma cells. Int J Cancer 33: 677–681, 1984

    Google Scholar 

  41. Yung WK, Kyritsis AP, Gleason MJ, Levin VA: Treatment of recurrent malignant gliomas with high-dose 13-cis-retinoic acid. Clin Cancer Res 2: 1931–1935, 1996

    Google Scholar 

  42. Elstner E, Williamson EA, Zang C, Fritz J, Heber D, Fenner M, Possinger K, Koeffler HP: Novel therapeutic approach: ligands for PPARgamma and retinoid receptors induce apoptosis in bcl-2-positive human breast cancer cells. Breast Cancer Res Treat 74: 155–165, 2002

    Google Scholar 

  43. Gavrieli Y, Sherman Y, Ben Sasson SA: Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119: 493–501, 1992

    Google Scholar 

  44. Stadelmann C, Bruck W, Bancher C, Jellinger K, Lassmann H: Alzheimer disease: DNA fragmentation indicates increased neuronal vulnerability, but not apoptosis. J Neuropathol Exp Neurol 57: 456–464, 1998

    Google Scholar 

  45. PE Biosystems: Relative quantitation of gene expression. ABI Prism 7700 Sequence Detection System, 1997

  46. Debril MB, Renaud JP, Fajas L, Auwerx J: The pleiotropic functions of peroxisome proliferator-activated receptor gamma. J Mol Med 79: 30–47, 2001

    Google Scholar 

  47. Konopleva M, Andreeff M: Role of peroxisome proliferatoractivated receptor-gamma in hematologic malignancies. Curr Opin Hematol 9: 294–302, 2002.

    Google Scholar 

  48. Ikezoe T, Miller CW, Kawano S, Heaney A, Williamson EA, Hisatake J, Green E, Hofmann W, Taguchi H, Koeffler HP: Mutational analysis of the peroxisome proliferator-activated receptor gamma gene in human malignancies. Cancer Res 61: 5307–5310, 2001

    Google Scholar 

  49. Cullingford TE, Bhakoo K, Peuchen S, Dolphin CT, Patel R, Clark JB: Distribution of mRNAs encoding the peroxisome proliferator-activated receptor alpha, beta, and gamma and the retinoid X receptor alpha, beta, and gamma in rat central nervous system. J Neurochem 70: 1366–1375, 1998

    Google Scholar 

  50. Bouterfa H, Picht T, Kess D, Herbold C, Noll E, Black PM, Roosen K, Tonn JC: Retinoids inhibit human glioma cell proliferation and migration in primary cell cultures but not in established cell lines. Neurosurgery 46: 419–430, 2000 118

    Google Scholar 

  51. Toyota M, Miyazaki Y, Kitamura S, Nagasawa Y, Kiyohara T, Shinomura Y, Matsuzawa Y: Peroxisome proliferator-activated receptor gamma reduces the growth rate of pancreatic cancer cells through the reduction of cyclin D1. Life Sci 70: 1565–1575, 2002

    Google Scholar 

  52. Yin F, Wakino S, Liu Z, Kim S, Hsueh WA, Collins AR, Van Herle AJ, Law RE: Troglitazone inhibits growth of MCF-7 breast carcinoma cells by targeting G1 cell cycle regulators. Biochem Biophys Res Commun 286: 916–922, 2001

    Google Scholar 

  53. Guan YF, Zhang YH, Breyer RM, Davis L, Breyer MD: Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in human transitional bladder cancer and its role in inducing cell death. Neoplasia 1: 330–339, 1999

    Google Scholar 

  54. Rumi MA, Sato H, Ishihara S, Kawashima K, Hamamoto S, Kazumori H, Okuyama T, Fukuda R, Nagasue N, Kinoshita Y: Peroxisome proliferator-activated receptor gamma ligand-induced growth inhibition of human hepatocellular carcinoma. Br J Cancer 84: 1640–1647, 2001

    Google Scholar 

  55. Cesi V, Tanno B, Vitali R, Mancini C, Giuffrida ML, Calabretta B, Raschella G: Cyclin D1-dependent regulation of B-myb activity in early stages of neuroblastoma differentiation. Cell Death Differ 9: 1232–1239, 2002

    Google Scholar 

  56. Spinella MJ, Freemantle SJ, Sekula D, Chang JH, Christie AJ, Dmitrovsky E: Retinoic acid promotes ubiquitination and proteolysis of cyclin D1 during induced tumor cell differentiation. J Biol Chem 274: 22013–22018, 1999

    Google Scholar 

  57. Zhang D, Vuocolo S, Masciullo V, Sava T, Giordano A, Soprano DR, Soprano KJ: Cell cycle genes as targets of retinoid induced ovarian tumor cell growth suppression. Oncogene 20: 7935–7944, 2001

    Google Scholar 

  58. Zhu WY, Jones CS, Kiss A, Matsukuma K, Amin S, De Luca LM: Retinoic acid inhibition of cell cycle progression in MCF-7 human breast cancer cells. Exp Cell Res 234: 293–299, 1997

    Google Scholar 

  59. Nasi S, Ciarapica R, Jucker R, Rosati J, Soucek L: Making decisions through Myc. FEBS Lett 490: 153–162, 2001

    Google Scholar 

  60. Zajac-Kaye M: Myc oncogene: a key component in cell cycle regulation and its implication for lung cancer. Lung Cancer 34(Suppl. 2): S43–S46, 2001

    Google Scholar 

  61. Sears R, Ohtani K, Nevins JR: Identification of positively and negatively acting elements regulating expression of the E2F2 gene in response to cell growth signals. Mol Cell Biol 17: 5227–5235, 1997

    Google Scholar 

  62. King KL, Cidlowski JA: Cell cycle regulation and apoptosis. Annu Rev Physiol 60: 601–617, 1998

    Google Scholar 

  63. Chen GG, Lee JF, Wang SH, Chan UP, Ip PC, Lau WY: Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and NF-kappaB in human colon cancer. Life Sci 70: 2631–2646, 2002

    Google Scholar 

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Authors and Affiliations

  1. Division of Oncology/Hematology, Humboldt University, Berlin, Germany

    Chuanbing Zang, Marlies Wächter, Hongyu Liu, Maximilian G. Posch, Martin H. Fenner, Kurt Possinger & Elena Elstner

  2. Institute for Neuropathology, School of Medicine (Charité), Humboldt University, Berlin, Germany

    Christine Stadelmann & Andreas von Deimling

  3. Cedars Sinai Medical Center, UCLA, School of Medicine, Los Angeles, CA, USA

    Keith L. Black & H. Phillip Koeffler

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  1. Chuanbing Zang
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  2. Marlies Wächter
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  3. Hongyu Liu
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  4. Maximilian G. Posch
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  5. Martin H. Fenner
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  6. Christine Stadelmann
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  7. Andreas von Deimling
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  8. Kurt Possinger
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Zang, C., Wächter, M., Liu, H. et al. Ligands for PPARγ and RAR Cause Induction of Growth Inhibition and Apoptosis in Human Glioblastomas. J Neurooncol 65, 107–118 (2003). https://doi.org/10.1023/B:NEON.0000003728.80052.a8

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