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Ciglitazone Induces Caspase-Independent Apoptosis through Down-Regulation of XIAP and Survivin in Human Glioma Cells

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Abstract

Induction of apoptosis may be a promising therapeutic approach in cancer therapy. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists induce apoptosis in various cancer cells. However, the molecular mechanism remains to be defined. The present study was undertaken to determine the precise mechanism of cell death induced by ciglitazone, a synthetic PPARγ agonist, in A172 human glioma cells. Ciglitazone resulted in a concentration- and time-dependent apoptotic cell death. Similar results were obtained with troglitazone, another synthetic PPARγ agonist. Ciglitazone induced reactive oxygen species (ROS) generation and ciglitazone-induced cell death was prevented by the antioxidant N-acetylcysteine, suggesting an important role of ROS generation in the ciglitazone-induced cell death. The cell death induced by ciglitazone was inhibited by the PPARγ antagonist GW9662. Although ciglitazone treatment caused a transient activation of extracellular signal-regulated kinase (ERK) and p38, the ciglitazone-induced cell death was not affected by inhibitors of these kinses. Ciglitazone caused a loss of mitochondrial membrane potential and its effect was prevented by N-acetylcysteine and GW9662. The specific inhibitor of caspases-3 DEVD-CHO and the general caspase inhibitor z-DEVD-FMK did not exert the protective effect against the ciglitazone-induced cell death and caspase-3 activity also was not altered by ciglitazone. The ciglitazone-induced cell death was accompanied by down-regulation of XIAP and Survivin, but not by release of apoptosis-inducing factor. Taken together, these findings suggest that down-regulation of XIAP and Survivin may play an active role in mediating a caspase-independent and -PPARγ-dependent cell death induced by ciglitazone in A172 human glioma cells. These data may provide a novel insight into potential therapeutic strategies for treatment of glioblastoma.

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References

  1. Ohgaki H, Kleihues P (2005) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64(6):479–489

    PubMed  CAS  Google Scholar 

  2. DeAngelis LM (2001) Brain tumors. N Engl J Med 344(2):114–123

    Article  PubMed  CAS  Google Scholar 

  3. Johnstone RW, Ruefli AA, Lowe SW (2002) Apoptosis: a link between cancer genetics and chemotherapy. Cell 108(2):153–164

    Article  PubMed  CAS  Google Scholar 

  4. Chen F, Wang M, O’Connor JP, He M, Tripathi T, Harrison LE (2003) Phosphorylation of PPARgamma via active ERK1/2 leads to its physical association with p65 and inhibition of NF-kappabeta. J Cell Biochem 90(4):732–744

    Article  PubMed  CAS  Google Scholar 

  5. Piva R, Gianferretti P, Ciucci A, Taulli R, Belardo G, Santoro MG (2005) 15-Deoxy-{Delta}12,14-prostaglandin J2 induces apoptosis in human malignant B cells: an effect associated with inhibition of NF-{kappa}B activity and down-regulation of antiapoptotic proteins. Blood 105(4):1750–1758

    Article  PubMed  CAS  Google Scholar 

  6. Clay CE, Monjazeb A, Thorburn J, Chilton FH, High KP (2002) 15-Deoxy-delta12,14-prostaglandin J2-induced apoptosis does not require PPARgamma in breast cancer cells. J Lipid Res 43(11):1818–1828

    Article  PubMed  CAS  Google Scholar 

  7. Grommes C, Landreth GE, Schlegel U, Heneka MT (2005) The nonthiazolidinedione tyrosine-based peroxisome proliferator-activated receptor gamma ligand GW7845 induces apoptosis and limits migration and invasion of rat and human glioma cells. J Pharmacol Exp Ther 313(2):806–813

    Article  PubMed  CAS  Google Scholar 

  8. Yamakawa-Karakida N, Sugita K, Inukai T, Goi K, Nakamura M, Uno K, Sato H, Kagami K, Barker N, Nakazawa S (2002) Ligand activation of peroxisome proliferator-activated receptor gamma induces apoptosis of leukemia cells by down-regulating the c-myc gene expression via blockade of the Tcf-4 activity. Cell Death Differ 9(5):513–526

    Article  PubMed  CAS  Google Scholar 

  9. Zander T, Kraus JA, Grommes C, Schlegel U, Feinstein D, Klockgether T, Landreth G, Koenigsknecht J, Heneka MT (2002) Induction of apoptosis in human and rat glioma by agonists of the nuclear receptor PPARgamma. J Neurochem 81(5):1052–1060

    Article  PubMed  CAS  Google Scholar 

  10. Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Partridge JB, Holden SA, Chen LB, Singer S, Fletcher C, Spiegelman BM (1998) Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat Med 4(9):1046–1052

    Article  PubMed  CAS  Google Scholar 

  11. Ni T, Li W, Zou F (2005) The ubiquitin ligase ability of IAPs regulates apoptosis. IUBMB Life 57(12):779–785

    Article  PubMed  CAS  Google Scholar 

  12. Liston P, Young SS, Mackenzie AE, Korneluk RG (1997) Life and death decisions: the role of the IAPs in modulating programmed cell death. Apoptosis 2(5):423–441

    Article  PubMed  CAS  Google Scholar 

  13. Ambrosini G, Adida C, Altieri DC (1997) A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3(8):917–921

    Article  PubMed  CAS  Google Scholar 

  14. Altieri DC, Marchisio PC (1999) Survivin apoptosis: an interloper between cell death and cell proliferation in cancer. Lab Invest 79(11):1327–1333

    PubMed  CAS  Google Scholar 

  15. Fong WG, Liston P, Rajcan-Separovic E, St Jean M, Craig C, Korneluk RG (2000) Expression and genetic analysis of XIAP-associated factor 1 (XAF1) in cancer cell lines. Genomics 70(1):113–122

    Article  PubMed  CAS  Google Scholar 

  16. Levkau B, Garton KJ, Ferri N, Kloke K, Nofer JR, Baba HA, Raines EW, Breithardt G (2001) xIAP induces cell-cycle arrest and activates nuclear factor-kappaB: new survival pathways disabled by caspase-mediated cleavage during apoptosis of human endothelial cells. Circ Res 88(3):282–290

    PubMed  CAS  Google Scholar 

  17. Fukuda S, Pelus LM (2006) Survivin, a cancer target with an emerging role in normal adult tissues. Mol Cancer Ther 5(5):1087–1098

    Article  PubMed  CAS  Google Scholar 

  18. Tamm I, Kornblau SM, Segall H, Krajewski S, Welsh K, Kitada S, Scudiero DA, Tudor G, Qui YH, Monks A, Andreeff M, Reed JC (2000) Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res 6(5):1796–1803

    PubMed  CAS  Google Scholar 

  19. Chakravarti A, Noll E, Black PM, Finkelstein DF, Finkelstein DM, Dyson NJ, Loeffler JS (2002) Quantitatively determined survivin expression levels are of prognostic value in human gliomas. J Clin Oncol 20(4):1063–1068

    Article  PubMed  CAS  Google Scholar 

  20. Kajiwara Y, Yamasaki F, Hama S, Yahara K, Yoshioka H, Sugiyama K, Arita K, Kurisu K (2003) Expression of survivin in astrocytic tumors: correlation with malignant grade and prognosis. Cancer 97(4):1077–1083

    Article  PubMed  Google Scholar 

  21. Denizot F, Lang R (1986) Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Methods 89(2):271–277

    Article  PubMed  CAS  Google Scholar 

  22. Pastorino JG, Chen ST, Tafani M, Snyder JW, Farber JL (1998) The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition. J Biol Chem 273(13):7770–7775

    Article  PubMed  CAS  Google Scholar 

  23. Birbes H, Bawab SE, Obeid LM, Hannun YA (2002) Mitochondria and ceramide: intertwined roles in regulation of apoptosis. Adv Enzyme Regul 42:113–129

    Article  PubMed  CAS  Google Scholar 

  24. Cohen GM (1997) Caspases: the executioners of apoptosis. Biochem J 326:1–16

    PubMed  CAS  Google Scholar 

  25. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397(6718):441–446

    Article  PubMed  CAS  Google Scholar 

  26. Perez-Ortiz JM, Tranque P, Vaquero CF, Domingo B, Molina F, Calvo S, Jordan J, Cena V, Llopis J (2004) Glitazones differentially regulate primary astrocyte and glioma cell survival. Involvement of reactive oxygen species and peroxisome proliferator-activated receptor-gamma. J Biol Chem 279(10):8976–8985

    Article  PubMed  CAS  Google Scholar 

  27. Rovin BH, Wilmer WA, Lu L, Doseff AI, Dixon C, Kotur M, Hilbelink T (2002) 15-Deoxy-Delta12,14-prostaglandin J2 regulates mesangial cell proliferation and death. Kidney Int 61(4):1293–1302

    Article  PubMed  CAS  Google Scholar 

  28. Martindale JL, Holbrook NJ (2002) Cellular response to oxidative stress: Signaling for suicide and survival. J Cell Physiol 192:1–15

    Article  PubMed  CAS  Google Scholar 

  29. Narayanan PK, Hart T, Elcock F, Zhang C, Hahn L, McFarland D, Schwartz L, Morgan DG, Bugelski P (2003) Troglitazone-induced intracellular oxidative stress in rat hepatoma cells: a flow cytometric assessment. Cytometry A 52(1):28–35

    Article  PubMed  CAS  Google Scholar 

  30. Lennon AM, Ramauge M, Dessouroux A, Pierre M (2002) MAP kinase cascades are activated in astrocytes and preadipocytes by 15-deoxy-Delta(12-14)-prostaglandin J(2) and the thiazolidinedione ciglitazone through peroxisome proliferator activator receptor gamma-independent mechanisms involving reactive oxygenated species. J Biol Chem 277(33):29681–29685

    Article  PubMed  CAS  Google Scholar 

  31. Kondo M, Oya-Ito T, Kumagai T, Osawa T, Uchida K (2001) Cyclopentenone prostaglandins as potential inducers of intracellular oxidative stress. J Biol Chem 276(15):12076–12083

    Article  PubMed  CAS  Google Scholar 

  32. Li L, Tao J, Davaille J, Feral C, Mallat A, Rieusset J, Vidal H, Lotersztajn S (2001) 15-deoxy-Delta 12,14-prostaglandin J2 induces apoptosis of human hepatic myofibroblasts. A pathway involving oxidative stress independently of peroxisome-proliferator-activated receptors. J Biol Chem 276(41):38152–38158

    PubMed  CAS  Google Scholar 

  33. Atarod EB, Kehrer JP (2004) Dissociation of oxidant production by peroxisome proliferator-activated receptor ligands from cell death in human cell lines. Free Radic Biol Med 37(1):36–47

    Article  PubMed  CAS  Google Scholar 

  34. Ward C, Dransfield I, Murray J, Farrow SN, Haslett C, Rossi AG (2002) Prostaglandin D2 and its metabolites induce caspase-dependent granulocyte apoptosis that is mediated via inhibition of I kappa B alpha degradation using a peroxisome proliferator-activated receptor-gamma-independent mechanism. J Immunol 168(12):6232–6243

    PubMed  CAS  Google Scholar 

  35. Shan ZZ, Masuko-Hongo K, Dai SM, Nakamura H, Kato T, Nishioka K (2004) A potential role of 15-deoxy-delta(12,14)-prostaglandin J2 for induction of human articular chondrocyte apoptosis in arthritis. J Biol Chem 279(36):37939–37950

    Article  PubMed  CAS  Google Scholar 

  36. Teruel T, Hernandez R, Benito M, Lorenzo M (2003) Rosiglitazone and retinoic acid induce uncoupling protein-1 (UCP-1) in a p38 mitogen-activated protein kinase-dependent manner in fetal primary brown adipocytes. J Biol Chem 278(1):263–269

    Article  PubMed  CAS  Google Scholar 

  37. Gardner OS, Dewar BJ, Earp HS, Samet JM, Graves LM (2003) Dependence of peroxisome proliferator-activated receptor ligand-induced mitogen-activated protein kinase signaling on epidermal growth factor receptor transactivation. J Biol Chem 278(47):46261–46269

    Article  PubMed  CAS  Google Scholar 

  38. Kim EJ, Park KS, Chung SY, Sheen YY, Moon DC, Song YS, Kim KS, Song S, Yun YP, Lee MK, Oh KW, Yoon do Y, Hong JT (2003) Peroxisome proliferator-activated receptor-gamma activator 15-deoxy-Delta12,14-prostaglandin J2 inhibits neuroblastoma cell growth through induction of apoptosis: association with extracellular signal-regulated kinase signal pathway. J Pharmacol Exp Ther 307(2):505–517

    Article  PubMed  CAS  Google Scholar 

  39. Padilla J, Kaur K, Cao HJ, Smith TJ, Phipps RP (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 165(12):6941–6948

    PubMed  CAS  Google Scholar 

  40. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270(5240):1326–1331

    Article  PubMed  CAS  Google Scholar 

  41. Cobb MH (1999) MAP kinase pathways. Prog Biophys Mol Biol 71(3-4):479–500

    Article  PubMed  CAS  Google Scholar 

  42. Choi BK, Choi CH, Oh HL, Kim YK (2004) Role of ERK activation in cisplatin-induced apoptosis in A172 human glioma cells. NeuroToxicology 25:915–924

    Article  PubMed  CAS  Google Scholar 

  43. Lee WC, Choi CH, Cha SH, Oh HL, Kim YK (2005) Role of ERK in hydrogen peroxide-induced cell death of human glioma cells. Neurochem Res 30:263–270

    Article  PubMed  CAS  Google Scholar 

  44. Bhat NR, Zhang P (1999) Hydrogen peroxide activation of multiple mitogen-activated protein kinases in an oligodendrocyte cell line: role of extracellular signal-regulated kinase in hydrogen peroxide-induced cell death. J Neurochem 72(1):112–119

    Article  PubMed  CAS  Google Scholar 

  45. Kim YK, Kim HJ, Kwon CH, Kim JH, Woo JS, Jung JS, Kim JM (2005) Role of ERK activation in cisplatin-induced apoptosis in OK renal epithelial cells. J Appl Toxicol 25:374–382

    Article  PubMed  CAS  Google Scholar 

  46. Pastorino JG, Snyder JW, Serroni A, Hoek JB, Farber JL (1993) Cyclosporin and carnitine prevent the anoxic death of cultured hepatocytes by inhibiting the mitochondrial permeability transition. J Biol Chem 268(19): 13791–13798

    PubMed  CAS  Google Scholar 

  47. Kroemer G, Dallaporta B, Resche-Rigon M (1998) The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol 60:619–642

    Article  PubMed  CAS  Google Scholar 

  48. Tatton WG, Olanow CW (1999) Apoptosis in neurodegenerative diseases: the role of mitochondria. Biochim Biophys Acta 1410(2):195–213

    Article  PubMed  CAS  Google Scholar 

  49. Pandhare J, Cooper SK, Phang JM (2006) Proline oxidase, a proapoptotic gene, is induced by troglitazone: evidence for both peroxisome proliferator-activated receptor gamma-dependent and -independent mechanisms. J Biol Chem 281(4):2044–2052

    Article  PubMed  CAS  Google Scholar 

  50. Hassouna I, Wickert H, Zimmermann M, Gillardon F (1996) Increase in bax expression in substantia nigra following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment of mice. Neurosci Lett 204(1–2):85–88

    Article  PubMed  CAS  Google Scholar 

  51. Yin C, Knudson CM, Korsmeyer SJ, Van Dyke T (1997) Bax suppresses tumorigenesis and stimulates apoptosis in vivo. Nature 385(6617):637–640

    Article  PubMed  CAS  Google Scholar 

  52. Antonsson B, Montessuit S, Lauper S, Eskes R, Martinou JC (2000) Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. Biochem J 345(Pt 2):271–278

    Article  PubMed  CAS  Google Scholar 

  53. Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281(5381):1309–1312

    Article  PubMed  CAS  Google Scholar 

  54. Desagher S, Martinou JC (2000) Mitochondria as the central control point of apoptosis. Trends Cell Biol 10(9):369–377

    Article  PubMed  CAS  Google Scholar 

  55. Tsuchiya T, Shimizu H, Shimomura K, Mori M (2003) Troglitazone inhibits isolated cell proliferation, and induces apoptosis in isolated rat mesangial cells. Am J Nephrol 23(4):222–228

    Article  PubMed  CAS  Google Scholar 

  56. Okura T, Nakamura M, Takata Y, Watanabe S, Kitami Y, Hiwada K (2000) Troglitazone induces apoptosis via the p53 and Gadd45 pathway in vascular smooth muscle cells. Eur J Pharmacol 407(3):227–235

    Article  PubMed  CAS  Google Scholar 

  57. Shen ZN, Nishida K, Doi H, Oohashi T, Hirohata S, Ozaki T, Yoshida A, Ninomiya Y, Inoue H (2005) Suppression of chondrosarcoma cells by 15-deoxy-Delta 12,14-prostaglandin J2 is associated with altered expression of Bax/Bcl-xL and p21. Biochem Biophys Res Commun 328(2):375–382

    Article  PubMed  CAS  Google Scholar 

  58. Liu JJ, Huang RW, Lin DJ, Peng J, Wu XY, Lin Q, Pan XL, Song YQ, Zhang MH, Hou M, Chen F (2005) Expression of survivin and bax/bcl-2 in peroxisome proliferator activated receptor-gamma ligands induces apoptosis on human myeloid leukemia cells in vitro. Ann Oncol 16(3):455–459

    Article  PubMed  CAS  Google Scholar 

  59. Kim SH, Yoo CI, Kim HT, Park JY, Kwon CH, Kim YK (2006) Activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) induces cell death through MAPK-dependent mechanism in osteoblastic cells. Toxicol Appl Pharmacol 215:198–207

    Article  PubMed  CAS  Google Scholar 

  60. Schultze K, Bock B, Eckert A, Oevermann L, Ramacher D, Wiestler O, Roth W (2006) Troglitazone sensitizes tumor cells to TRAIL-induced apoptosis via down-regulation of FLIP and Survivin. Apoptosis 11:1503–1512

    Article  PubMed  CAS  Google Scholar 

  61. Ray DM, Akbiyik F, Bernstein SH, Phipps RP (2005) CD40 engagement prevents peroxisome proliferator-activated receptor gamma agonist-induced apoptosis of B lymphocytes and B lymphoma cells by an NF-kappaB-dependent mechanism. J Immunol 174(7):4060–4069

    PubMed  CAS  Google Scholar 

  62. Pignatelli M, Sanchez-Rodriguez J, Santos A, Perez-Castillo A (2005) 15-deoxy-Delta-12,14-prostaglandin J2 induces programmed cell death of breast cancer cells by a pleiotropic mechanism. Carcinogenesis 26(1):81–92

    Article  PubMed  CAS  Google Scholar 

  63. Penninger JM, Kroemer G (2003) Mitochondria, AIF and caspases–rivaling for cell death execution. Nat Cell Biol 5(2):97–99

    Article  PubMed  CAS  Google Scholar 

  64. Silke J, Hawkins CJ, Ekert PG, Chew J, Day CL, Pakusch M, Verhagen AM, Vaux DL (2002) The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase 3- and caspase 9-interacting sites. J Cell Biol 157(1):115–124

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by the MRC program of MOST/KOSEF (R13-2005—009) and the 21st Century Frontier/Stem Cell Research Committee (SC3130) in Korea.

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  1. Department of Neurosurgery, College of Medicine, Pusan National University, Pusan, 602-739, Korea

    Dong Wan Kang & Chang Hwa Choi

  2. Department of Physiology, College of Medicine, Pusan National University, Pusan, 602-739, Korea

    Ji Yeon Park, Soo Kyung Kang & Yong Keun Kim

  3. MRC for Ischemic Tissue Regeneration, College of Medicine, Pusan National University, Pusan, 602-739, Korea

    Yong Keun Kim

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Kang, D.W., Choi, C.H., Park, J.Y. et al. Ciglitazone Induces Caspase-Independent Apoptosis through Down-Regulation of XIAP and Survivin in Human Glioma Cells. Neurochem Res 33, 551–561 (2008). https://doi.org/10.1007/s11064-007-9475-x

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