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Research Article
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Published Online: 30 July 2010

The Antioxidant Effects of Genistein Are Associated with AMP-Activated Protein Kinase Activation and PTEN Induction in Prostate Cancer Cells

Publication: Journal of Medicinal Food
Volume 13, Issue Number 4

Abstract

Epidemiological evidence suggests a lower incidence of prostate cancer in Asian countries, where soy products are more frequently consumed than in Western countries, indicating that isoflavones from soy have chemopreventive activities in prostate cells. Here, we tested the effects of the soy isoflavone genistein on antioxidant enzymes in DU145 prostate cancer cells. Genistein significantly decreased reactive oxygen species levels and induced the expression of the antioxidant enzymes manganese (Mn) superoxide dismutase (SOD) and catalase, which were associated with AMP-activated protein kinase (AMPK) and phosphatase and tensin homolog deleted from chromosome 10 (PTEN) pathways. The induced expression of catalase, MnSOD, and PTEN were attenuated by pretreatment with a pharmacological inhibitor for AMPK, indicating the effects of genistein primarily depend on AMPK. Furthermore, PTEN is essential for genistein activity, as shown by PTEN transfection in PTEN-deficient PC3 cells. Thus, genistein induces antioxidant enzymes through AMPK activation and increased PTEN expression.

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References

1.
Hebert JRHurley TGOlendzki BCTeas JMa YHampl JS. Nutritional and socioeconomic factors in relation to prostate cancer mortality: a cross-national studyJ Natl Cancer Inst1998901637-1647. 1. Hebert JR, Hurley TG, Olendzki BC, Teas J, Ma Y, Hampl JS: Nutritional and socioeconomic factors in relation to prostate cancer mortality: a cross-national study. J Natl Cancer Inst 1998;90:1637–1647.
2.
Jacobsen BKKnutsen SFFraser GE. Does high soy milk intake reduce prostate cancer incidence? The Adventist health study (United States)Cancer Causes Control19989553-557. 2. Jacobsen BK, Knutsen SF, Fraser GE: Does high soy milk intake reduce prostate cancer incidence? The Adventist health study (United States). Cancer Causes Control 1998;9:553–557.
3.
Kurahashi NIwasaki MSasazuki SOtani TInoue MTsugane S. Soy product and isoflavone consumption in relation to prostate cancer in Japanese menCancer Epidemiol Biomarkers Prev200716538-545. 3. Kurahashi N, Iwasaki M, Sasazuki S, Otani T, Inoue M, Tsugane S: Soy product and isoflavone consumption in relation to prostate cancer in Japanese men. Cancer Epidemiol Biomarkers Prev 2007;16:538–545.
4.
Adlercreutz CHGoldin BRGorbach SLHöckerstedt KAWatanabe SHämäläinen EKMarkkanen MHMäkelä THWähälä KTAdlercreutz T. Soybean phytoestrogen intake and cancer riskJ Nutr19951253 Suppl757S-770SErratum in J Nutr 1995;125:1960. 4. Adlercreutz CH, Goldin BR, Gorbach SL, Höckerstedt KA, Watanabe S, Hämäläinen EK, Markkanen MH, Mäkelä TH, Wähälä KT, Adlercreutz T: Soybean phytoestrogen intake and cancer risk. J Nutr 1995;125(3 Suppl):757S–770S. Erratum in J Nutr 1995;125:1960.
5.
Sarkar FHLi Y. Mechanisms of cancer chemoprevention by soy isoflavone genisteinCancer Metastasis Rev200221265-280. 5. Sarkar FH, Li Y: Mechanisms of cancer chemoprevention by soy isoflavone genistein. Cancer Metastasis Rev 2002;21:265–280.
6.
Waite KASinden MREng C. Phytoestrogen exposure elevates PTEN levelsHum Mol Genet2005141457-1463. 6. Waite KA, Sinden MR, Eng C: Phytoestrogen exposure elevates PTEN levels. Hum Mol Genet 2005;14:1457–1463.
7.
Wang JEltoum IECarpenter MLamartiniere CA. Genistein mechanisms and timing of prostate cancer chemoprevention in Lobund-Wistar ratsAsian Pac J Cancer Prev200910143-150. 7. Wang J, Eltoum IE, Carpenter M, Lamartiniere CA: Genistein mechanisms and timing of prostate cancer chemoprevention in Lobund-Wistar rats. Asian Pac J Cancer Prev 2009;10:143–150.
8.
Steck PAPershouse MAJasser SAYung WKLin HLigon AHLangford LABaumgard MLHattier TDavis TFrye CHu RSwedlund BTeng DHTavtigian SV. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancersNat Genet199715356-362. 8. Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV: Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997;15:356–362.
9.
Sulis MLParsons R. PTEN: from pathology to biologyTrends Cell Biol200313478-483. 9. Sulis ML, Parsons R: PTEN: from pathology to biology. Trends Cell Biol 2003;13:478–483.
10.
Maehama TTaylor GSDixon JE. PTEN and myotubularin: novel phosphoinositide phosphatasesAnnu Rev Biochem200170247-279. 10. Maehama T, Taylor GS, Dixon JE: PTEN and myotubularin: novel phosphoinositide phosphatases. Annu Rev Biochem 2001;70:247–279.
11.
Stambolic VSuzuki Ade la Pompa JLBrothers GMMirtsos CSasaki TRuland JPenninger JMSiderovski DPMak TW. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTENCell19989529-39. 11. Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW: Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 1998;95:29–39.
12.
Maehama TDixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphateJ Biol Chem199827313375-13378. 12. Maehama T, Dixon JE: The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998;273:13375–13378.
13.
Datta SRBrunet AGreenberg ME. Cellular survival: a play in three AktsGenes Dev1999132905-2927. 13. Datta SR, Brunet A, Greenberg ME: Cellular survival: a play in three Akts. Genes Dev 1999;13:2905–2927.
14.
Huo YYLi GDuan RFGou QFu CLHu YCSong BQYang ZHWu DCZhou PK. PTEN deletion leads to deregulation of antioxidants and increased oxidative damage in mouse embryonic fibroblastsFree Radic Biol Med2008441578-1591. 14. Huo YY, Li G, Duan RF, Gou Q, Fu CL, Hu YC, Song BQ, Yang ZH, Wu DC, Zhou PK: PTEN deletion leads to deregulation of antioxidants and increased oxidative damage in mouse embryonic fibroblasts. Free Radic Biol Med 2008;44:1578–1591.
15.
Marsin ASBouzin CBertrand LHue L. The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinaseJ Biol Chem200227730778-30783. 15. Marsin AS, Bouzin C, Bertrand L, Hue L: The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. J Biol Chem 2002;277:30778–30783.
16.
Choi SLKim SJLee KTKim JMu JBirnbaum MJSoo Kim SHa J. The regulation of AMP-activated protein kinase by H2O2Biochem Biophys Res Commun200128792-97. 16. Choi SL, Kim SJ, Lee KT, Kim J, Mu J, Birnbaum MJ, Soo Kim S, Ha J: The regulation of AMP-activated protein kinase by H2O2. Biochem Biophys Res Commun 2001;287:92–97.
17.
Hwang JTHa JPark OJ. Combination of 5-fluorouracil and genistein induces apoptosis synergistically in chemo-resistant cancer cells through the modulation of AMPK and COX-2 signaling pathwaysBiochem Biophys Res Commun2005332433-440. 17. Hwang JT, Ha J, Park OJ: Combination of 5-fluorouracil and genistein induces apoptosis synergistically in chemo-resistant cancer cells through the modulation of AMPK and COX-2 signaling pathways. Biochem Biophys Res Commun 2005;332:433–440.
18.
Hwang JTPark IJShin JILee YKLee SKBaik HWHa JPark OJ. Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinaseBiochem Biophys Res Commun2005338694-699. 18. Hwang JT, Park IJ, Shin JI, Lee YK, Lee SK, Baik HW, Ha J, Park OJ: Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinase. Biochem Biophys Res Commun 2005;338:694–699.
19.
Hawley SADavison MWoods ADavies SPBeri RKCarling DHardie DG. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinaseJ Biol Chem199627127879-27887. 19. Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, Hardie DG: Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem 1996;271:27879–27887.
20.
Malins DCJohnson PMBarker EAPolissar NLWheeler TMAnderson KM. Cancer-related changes in prostate DNA as men age and early identification of metastasis in primary prostate tumorsProc Natl Acad Sci USA20031005401-5406. 20. Malins DC, Johnson PM, Barker EA, Polissar NL, Wheeler TM, Anderson KM: Cancer-related changes in prostate DNA as men age and early identification of metastasis in primary prostate tumors. Proc Natl Acad Sci USA 2003;100:5401–5406.
21.
Fruehauf JPMeyskens FL Jr. Reactive oxygen species: a breath of life or death?Clin Cancer Res200713789-794. 21. Fruehauf JP, Meyskens FL Jr: Reactive oxygen species: a breath of life or death? Clin Cancer Res 2007;13:789–794.
22.
Jung SNYang WKKim JKim HSKim EJYun HPark HKim SSChoe WKang IHa J. Reactive oxygen species stabilize hypoxia-inducible factor-1 alpha protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cellsCarcinogenesis200829713-721. 22. Jung SN, Yang WK, Kim J, Kim HS, Kim EJ, Yun H, Park H, Kim SS, Choe W, Kang I, Ha J: Reactive oxygen species stabilize hypoxia-inducible factor-1 alpha protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells. Carcinogenesis 2008;29:713–721.
23.
Klaunig JEKamendulis LM. The role of oxidative stress in carcinogenesisAnnu Rev Pharmacol Toxicol200444239-267. 23. Klaunig JE, Kamendulis LM: The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol 2004;44:239–267.
24.
Bostwick DGAlexander EESingh RShan AQian JSantella RMOberley LWYan TZhong WJiang XOberley TD. Antioxidant enzyme expression and reactive oxygen species damage in prostatic intraepithelial neoplasia and cancerCancer200089123-134. 24. Bostwick DG, Alexander EE, Singh R, Shan A, Qian J, Santella RM, Oberley LW, Yan T, Zhong W, Jiang X, Oberley TD: Antioxidant enzyme expression and reactive oxygen species damage in prostatic intraepithelial neoplasia and cancer. Cancer 2000;89:123–134.
25.
Banerjee SLi YWang ZSarkar FH. Multi-targeted therapy of cancer by genisteinCancer Lett2008269226-242. 25. Banerjee S, Li Y, Wang Z, Sarkar FH: Multi-targeted therapy of cancer by genistein. Cancer Lett 2008;269:226–242.
26.
Suzuki KKoike HMatsui HOno YHasumi MNakazato HOkugi HSekine YOki KIto KYamamoto TFukabori YKurokawa KYamanaka H. Genistein, a soy isoflavone, induces glutathione peroxidase in the human prostate cancer cell lines LNCaP and PC-3Int J Cancer200299846-852. 26. Suzuki K, Koike H, Matsui H, Ono Y, Hasumi M, Nakazato H, Okugi H, Sekine Y, Oki K, Ito K, Yamamoto T, Fukabori Y, Kurokawa K, Yamanaka H: Genistein, a soy isoflavone, induces glutathione peroxidase in the human prostate cancer cell lines LNCaP and PC-3. Int J Cancer 2002;99:846–852.
27.
Cai QWei H. Effect of dietary genistein on antioxidant enzyme activities in SENCA miceNutr Cancer1996251-7. 27. Cai Q, Wei H: Effect of dietary genistein on antioxidant enzyme activities in SENCA mice. Nutr Cancer 1996;25:1–7.
28.
Stambolic VMacpherson DSas DLin YSnow BJang YBenchimol SMak TW. Regulation of PTEN transcription by p53Mol Cell20018317-325. 28. Stambolic V, Macpherson D, Sas D, Lin Y, Snow B, Jang Y, Benchimol S, Mak TW: Regulation of PTEN transcription by p53. Mol Cell 2001;8:317–325.
29.
Patel LPass ICoxon PDownes CPSmith SAMacphee CH. Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTENCurr Biol200111764-768. 29. Patel L, Pass I, Coxon P, Downes CP, Smith SA, Macphee CH: Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN. Curr Biol 2001;11:764–768.
30.
Virolle TAdamson EDBaron VBirle DMercola DMustelin Tde Belle I. The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalingNat Cell Biol200131124-1128. 30. Virolle T, Adamson ED, Baron V, Birle D, Mercola D, Mustelin T, de Belle I: The Egr-1 transcription factor directly activates PTEN during irradiation-induced signaling. Nat Cell Biol 2001;3:1124–1128.
31.
Lehmann JMMoore LBSmith-Oliver TAWilkison WOWillson TMKliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPAR γ)J Biol Chem199527012953-12956. 31. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA: An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPAR γ). J Biol Chem 1995;270:12953–12956.
32.
Han SRoman J. Rosiglitazone suppresses human lung carcinoma cell growth through PPARgamma-dependent and PPARgamma-independent signal pathwaysMol Cancer Ther20065430-437. 32. Han S, Roman J: Rosiglitazone suppresses human lung carcinoma cell growth through PPARgamma-dependent and PPARgamma-independent signal pathways. Mol Cancer Ther 2006;5:430–437.
33.
Teresi REShaiu CWChen CSChatterjee VKWaite KAEng C. Increased PTEN expression due to transcriptional activation of PPARgamma by lovastatin and rosiglitazoneInt J Cancer20061182390-2398. 33. Teresi RE, Shaiu CW, Chen CS, Chatterjee VK, Waite KA, Eng C: Increased PTEN expression due to transcriptional activation of PPARgamma by lovastatin and rosiglitazone. Int J Cancer 2006;118:2390–2398.
34.
Dang ZCAudinot VPapapoulos SEBoutin JALöwik CW. Peroxisome proliferator-activated receptor gamma (PPARgamma) as a molecular target for the soy phytoestrogen genisteinJ Biol Chem2003278962-967. 34. Dang ZC, Audinot V, Papapoulos SE, Boutin JA, Löwik CW: Peroxisome proliferator-activated receptor gamma (PPARgamma) as a molecular target for the soy phytoestrogen genistein. J Biol Chem 2003;278:962–967.
35.
Cui WGu FHu KQ. Effects and mechanisms of silibinin on human hepatocellular carcinoma xenografts in nude miceWorld J Gastroenterol2009151943-1950. 35. Cui W, Gu F, Hu KQ: Effects and mechanisms of silibinin on human hepatocellular carcinoma xenografts in nude mice. World J Gastroenterol 2009;15:1943–1950.

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Published In

cover image Journal of Medicinal Food
Journal of Medicinal Food
Volume 13Issue Number 4August 2010
Pages: 815 - 820
PubMed: 20673057

History

Published in print: August 2010
Published online: 30 July 2010
Accepted: 28 April 2010
Received: 3 December 2009

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    Affiliations

    Chang Eun Park
    *
    Department of East-West Medicine, Graduate School; Kyung Hee University, Seoul, Republic of Korea
    Hee Yun*
    Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
    Eun-Byul Lee
    Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
    Byung-Il Min
    Department of East-West Medicine, Graduate School; Kyung Hee University, Seoul, Republic of Korea
    Hyunsu Bae
    Department of Physiology, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
    Wonchae Choe
    Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
    Insug Kang
    Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
    Sung-Soo Kim
    Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Republic of Korea
    Joohun Ha
    Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Republic of Korea

    Notes

    Address correspondence to: Joohun Ha, Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea, E-mail: [email protected]

    Author Disclosure Statement

    No competing financial interests exist.

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