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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2010

Open Access 01-12-2010 | Research

Mitochondrial and endoplasmic reticulum stress pathways cooperate in zearalenone-induced apoptosis of human leukemic cells

Authors: Ratana Banjerdpongchai, Prachya Kongtawelert, Orawan Khantamat, Chantragan Srisomsap, Daranee Chokchaichamnankit, Pantipa Subhasitanont, Jisnuson Svasti

Published in: Journal of Hematology & Oncology | Issue 1/2010

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Abstract

Background

Zearalenone (ZEA) is a phytoestrogen from Fusarium species. The aims of the study was to identify mode of human leukemic cell death induced by ZEA and the mechanisms involved.

Methods

Cell cytotoxicity of ZEA on human leukemic HL-60, U937 and peripheral blood mononuclear cells (PBMCs) was performed by using 3-(4,5-dimethyl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Reactive oxygen species production, cell cycle analysis and mitochondrial transmembrane potential reduction was determined by employing 2',7'-dichlorofluorescein diacetate, propidium iodide and 3,3'-dihexyloxacarbocyanine iodide and flow cytometry, respectively. Caspase-3 and -8 activities were detected by using fluorogenic Asp-Glu-Val-Asp-7-amino-4-methylcoumarin (DEVD-AMC) and Ile-Glu-Thr-Asp-7-amino-4-methylcoumarin (IETD-AMC) substrates, respectively. Protein expression of cytochrome c, Bax, Bcl-2 and Bcl-xL was performed by Western blot. The expression of proteins was assessed by two-dimensional polyacrylamide gel-electrophoresis (PAGE) coupled with LC-MS2 analysis and real-time reverse transcription polymerase chain reaction (RT-PCR) approach.

Results

ZEA was cytotoxic to U937 > HL-60 > PBMCs and caused subdiploid peaks and G1 arrest in both cell lines. Apoptosis of human leukemic HL-60 and U937 cell apoptosis induced by ZEA was via an activation of mitochondrial release of cytochrome c through mitochondrial transmembrane potential reduction, activation of caspase-3 and -8, production of reactive oxygen species and induction of endoplasmic reticulum stress. Bax was up regulated in a time-dependent manner and there was down regulation of Bcl-xL expression. Two-dimensional PAGE coupled with LC-MS2 analysis showed that ZEA treatment of HL-60 cells produced differences in the levels of 22 membrane proteins such as apoptosis inducing factor and the ER stress proteins including endoplasmic reticulum protein 29 (ERp29), 78 kDa glucose-regulated protein, heat shock protein 90 and calreticulin, whereas only ERp29 mRNA transcript increased.

Conclusion

ZEA induced human leukemic cell apoptosis via endoplasmic stress and mitochondrial pathway.
Appendix
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Literature
1.
Nikov G, Hopkins N, Boue S, Alworth WL: Interactions of dietary estrogens with human estrogen receptors and the effect on estrogen receptor-estrogen response element complex formation. Environ Health Perspect. 2000, 108: 867-872.PubMedCentralCrossRefPubMed
2.
Kuiper GG, Lemma JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JA: Interaction of estrogenic chemicals and phytoestrogens with estrogen receptors (beta). Endocrinology. 1998, 139: 4252-4263. 10.1210/en.139.10.4252.PubMed
3.
Janardhana GR, Rabeas KA, Shekar Shetty H: Mycotoxin contamination of maize grains grown in Karnataka (India). Food Chem Toxicol. 1999, 37: 863-868. 10.1016/S0278-6915(99)00067-8.CrossRefPubMed
4.
Okoye ZS: Stability of zearalenone in naturally contaminated corn during Nigerian traditional brewing. Food Addit Contam. 1987, 4: 57-59.CrossRefPubMed
5.
Reza Oveisi M, Hajimahmoodi M, Memarian S, Sadeghi N, Shoeibi S: Determination of zearalenone in corn flour and a cheese snack product using high-performance liquid chromatography with fluorescence detection. Food Addit Contam. 2005, 22: 443-448. 10.1080/02652030500073709.CrossRefPubMed
6.
Minervini F, Giannoccaro A, Cavallini A, Visconti A: Investigations on cellular proliferation induced by zearalenone and its derivatives in relation to the estrogenic parameters. Toxicol Lett. 2005, 159: 272-283. 10.1016/j.toxlet.2005.05.017.CrossRefPubMed
7.
Abid-Essefi S, Baudrimont I, Hassen W, Ouanes Z, Mobio TA, Anane R, Creppy EE, Bacha H: DNA fragmentation, apoptosis and cell cycle arrest induced by zearalenone in cultured DOK, Vero and Caco-2 cells: prevention by vitamin E. Toxicology. 2003, 192: 237-248. 10.1016/S0300-483X(03)00329-9.CrossRefPubMed
8.
Ayed-Boussema I, Bouaziz C, Rjiba K, Valenti K, Laporte F, Bacha H, Hassen W: The mycotoxin Zearalenone induces apoptosis in human hepatocytes (HepG2) via p53-dependent mitochondrial signaling pathway. Toxicol In Vitro. 2008, 22: 1671-1680. 10.1016/j.tiv.2008.06.016.CrossRefPubMed
9.
Dias N, Bailly C: Drugs targeting mitochondrial functions to control tumor cell growth. Biochem Pharmacol. 2005, 70: 1-12. 10.1016/j.bcp.2005.03.021.CrossRefPubMed
10.
Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S, Peter M: Apoptosis signaling by death receptors. Eur J Biochem. 1998, 254: 439-459. 10.1046/j.1432-1327.1998.2540439.x.CrossRefPubMed
11.
Rao RV, Ellerby HM, Bredesen DE: Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ. 2004, 11: 372-380. 10.1038/sj.cdd.4401378.CrossRefPubMed
12.
Budihardjo I, Oliver H, Lutter M, Luo X, Wang X: Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol. 1999, 15: 269-290. 10.1146/annurev.cellbio.15.1.269.CrossRefPubMed
13.
Li UX, Kim CN, Yang J, Jemmerson R, Wang X: Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996, 86: 147-157. 10.1016/S0092-8674(00)80085-9.CrossRef
14.
Thorburn A: Death receptor-induced cell killing. Cell Signal. 2004, 16: 139-144. 10.1016/j.cellsig.2003.08.007.CrossRefPubMed
15.
Boyce M, Yuan J: Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ. 2006, 13: 363-373. 10.1038/sj.cdd.4401817.CrossRefPubMed
16.
Yamaguchi H, Wang HG: CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem. 2004, 279: 45495-45502. 10.1074/jbc.M406933200.CrossRefPubMed
17.
Johnson S, Michalak M, Opas M, Eggleton P: The ins and outs of calreticulin: from the ER lumen to the extracellular space. Trends Cell Biol. 2001, 11: 122-129. 10.1016/S0962-8924(01)01926-2.CrossRefPubMed
18.
Michalak M, Corbett EF, Mesaeli N, Nakamura K, Opas M: Calreticulin: one protein, one gene, many functions. Biochem J. 1999, 344: 281-292. 10.1042/0264-6021:3440281.PubMedCentralCrossRefPubMed
19.
Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE: Cell surface calreticulin initiates clearance of viable or apoptotic cells through transactivation of LRP on the phagocyte. Cell. 2005, 123: 321-334. 10.1016/j.cell.2005.08.032.CrossRefPubMed
20.
Obeid M, Tesniere A, Ghringhelli F, Fimia GM, Apetoh L, Perfettini JL: Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007, 13: 54-61. 10.1038/nm1523.CrossRefPubMed
21.
Apetoh L, Ghringhelli F, Tesniere A, Obeid M, Ortiz C, Criolo A: Toll-like receptor 4-dependent contribution of the immune system to anti-cancer chemo- and radiotherapy. Nat Med. 2007, 13: 1050-1059. 10.1038/nm1622.CrossRefPubMed
22.
Casares N, Pequignot MO, Tesniere A, Ghringhelli F, Roux S, Chaput N: Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med. 2005, 202: 1691-1701. 10.1084/jem.20050915.PubMedCentralCrossRefPubMed
23.
Srivastava PK: Heat shock protein-based novel immunotherapies. Drug News Perspect. 2000, 13: 517-522. 10.1358/dnp.2000.13.9.858479.CrossRefPubMed
24.
25.
Jimbo A, Fujita E, Kouroku Y, Ohnishi J, Inohara N, Kuida K, Sakamaki K, Yonchara S, Momoi T: ER stress induces caspase-8 activation, stimulating cytochrome c release and caspase-9 activation. Exp Cell Res. 2003, 283: 156-166. 10.1016/S0014-4827(02)00033-2.CrossRefPubMed
26.
Su WC, Chang SL, Chen TY, Chen JS, Tsao CJ: Comparison in in vitro growth-inhibitory activity of carboplatin and cisplatin on leukemic cells and hematopoietic progenitors: the myelosuppressive activity of carboplatin may be greater than its antileukemic effect. Jpn J Clin Oncol. 2002, 30: 562-567. 10.1093/jjco/hyd137.CrossRef
27.
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.CrossRefPubMed
28.
Gottlieb E, Armour SM, Harris MH, Thompson CB: Mitochondrial membrane potential regulates matrix configuration and cytochrome c release. Cell Death Differ. 2003, 10: 709-717. 10.1038/sj.cdd.4401231.CrossRefPubMed
29.
Roucou X, Montessuit S, Antonsson B, Martinou JC: Bax oligomerization in mitochondrial membranes requires tBid (caspase-8-cleaved Bid) and a mitochondrial protein. Biochem J. 2002, 368: 915-921. 10.1042/BJ20020972.PubMedCentralCrossRefPubMed
30.
Scorrano L, Korsmeyer SJ: Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem Biophys Res Commun. 2003, 304: 437-444. 10.1016/S0006-291X(03)00615-6.CrossRefPubMed
31.
Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH: Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ. 2000, 7: 1166-1173. 10.1038/sj.cdd.4400783.CrossRefPubMed
32.
Bouaziz C, Sharaf El Dein O, El Golli E, Abid-Essefi S, Brenner C, Lemaire C: Different apoptotic pathways induced by zearalenone, T-2 toxin and ochratoxin A in human hepatoma cells. Toxicology. 2008, 254: 19-28. 10.1016/j.tox.2008.08.020.CrossRefPubMed
33.
Bizyukin AV, Korkina LG, Velichkovskii BT: Comparative Use of 2,7-dichlorofluorescin diacetate, dihydrorhodamine 123, and hydroethidine to study oxidative metabolism in phagocytic cells. Bull Eksp Biol Med. 1995, 119: 347-351. 10.1007/BF02445889.CrossRef
34.
Silveira LR, Pereira-Da-Silva L, Juel C, Hellsten Y: Formation of hydrogen peroxide and nitric oxide in rat skeletal muscle cells during contractions. Free Radic Biol Med. 2003, 35: 455-464. 10.1016/S0891-5849(03)00271-5.CrossRefPubMed
35.
Picard D: Heat-shock protein 90, a chaperone for folding and regulation. Cell Mol Life Sci. 2002, 59: 1640-1648. 10.1007/PL00012491.CrossRefPubMed
36.
Zhang D, Armstrong JS: Bax and the mitochondrial permeability transition cooperate in the release of cytochrome c during endoplasmic reticulum-stress-induced apoptosis. Cell Death Differ. 2007, 14: 703-715. 10.1038/sj.cdd.4402072.CrossRefPubMed
37.
Tufi R, Panaretakis T, Bianchi K, Criollo A, Fazi B, Di Sano F, Tesniere A, Kepp O, Paterlini-Brechot P, Zitvogel L, Piacentini M, Szabadkai G, Kroemer G: Reduction of endoplasmic reticulum calcium ion levels favors plasma membrane surface exposure of calreticulin. Cell Death Differ. 2007, 14: 1-9. 10.1038/sj.cdd.4402064.CrossRef
38.
D'Mello JPF, Placinta CM, MacDonald AMC: Fusarium mycotoxins: a review of global animal health, welfare and reproductivity. Anim Feed Sci Technol. 1999, 78: 183-205.CrossRef
39.
Minervini F, Dell'Aquila ME, Maritato F, Minoia P, Visconti A: Toxic effects of the mycotoxin zearalenone and its derivatives on in vitro maturation of bovine oocytes and 17[beta]-estradiol levels in mural granulosa cell cultures. Toxicol In Vitro. 2001, 15: 489-495. 10.1016/S0887-2333(01)00068-6.CrossRefPubMed
40.
Lioi MB, Santoro A, Barbieri R, Salzano S, Ursini MV: Ochratoxin A and zearalenone: a comparative study on genotoxic effects and cell death induced in bovine lymphocytes. Mutat Res. 2004, 557: 19-27.CrossRefPubMed
41.
Vlata Z, Porichis F, Tzanakakis G, Tsatsakis A, Krambovitis E: A study of zearalenone cytotoxicity on human peripheral blood mononuclear cells. Toxicol Lett. 2006, 165: 274-281. 10.1016/j.toxlet.2006.05.001.CrossRefPubMed
42.
Kouadio JH, Mobio TA, Baudrimont I, Moukha S, Dano SD, Creppy EE: Comparative study of cytotoxicity and oxidative stress induced by deoxynivalenol, zearalenone or fumonisin B1 in human intestinal cell line Caco-2. Toxicology. 2005, 213: 56-65. 10.1016/j.tox.2005.05.010.CrossRefPubMed
43.
Jürgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D, Reed J: Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci USA. 1998, 95: 4997-5002.PubMedCentralCrossRefPubMed
44.
Antonsson B, Montessuit S, Lauper S, Eskes R, Martinou JC: Bax oligomerization is required for channel-forming activity in liposomes and to trigger cytochrome c release from mitochondria. Biochem J. 2000, 345: 271-278. 10.1042/0264-6021:3450271.PubMedCentralCrossRefPubMed
45.
Yang JC, Cortopassi GA: Induction of the mitochondrial permeability transition causes release of the apoptogenic factor cytochrome c. Free Radic Biol Med. 1998, 24: 624-631. 10.1016/S0891-5849(97)00367-5.CrossRefPubMed
46.
Bradham CA, Qian T, Streetz K, Trautwein C, Brenner DA, Lemasters JJ: The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release. Mol Cell Biol. 1998, 18: 6353-6364.PubMedCentralCrossRefPubMed
47.
Hara MR, Agrawal N, Kim SF, Cascio MB, Fujimuro M, Ozeki Y, Takahashi M, Cheah MJH, Tankou SK, Hester LD, Ferris CD, Hayward SD, Snyder SH, Sawa A: S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol. 2005, 7: 665-674. 10.1038/ncb1268.CrossRefPubMed
48.
Munro S, Pelham HR: A C-terminal signal prevents secretion of luminal ER proteins. Cell. 1987, 48: 899-907. 10.1016/0092-8674(87)90086-9.CrossRefPubMed
49.
Pelham HR: Evidence that luminal ER proteins are sorted from secreted proteins in a post-ER compartment. EMBO J. 1988, 7: 913-918.PubMedCentralPubMed
50.
51.
Othmen ZO, Golli EE, Abid-Essefi S, Bacha H: Cytotoxicity effects induced by Zearalenone metabolites, alpha Zearalenol and beta Zearalenol, on cultured Vero cells. Toxicology. 2008, 252: 72-77. 10.1016/j.tox.2008.07.065.CrossRefPubMed
Metadata
Title
Mitochondrial and endoplasmic reticulum stress pathways cooperate in zearalenone-induced apoptosis of human leukemic cells
Authors
Ratana Banjerdpongchai
Prachya Kongtawelert
Orawan Khantamat
Chantragan Srisomsap
Daranee Chokchaichamnankit
Pantipa Subhasitanont
Jisnuson Svasti
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2010
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/1756-8722-3-50

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