title: Oxidative stress adaptation in aggressive prostate cancer may be counteracted by the reduction of glutathione reductase.
abstract: Oxidative stress has been associated with prostate cancer development and progression due to an increase of reactive oxygen species (ROS). However, the mechanisms whereby ROS and the antioxidant system participate in cancer progression remain unclear. In order to clarify the influence of oxidative stress in prostate cancer progression, we performed this study in two human prostate cancer cell lines, PC3 and HPV10 (from metastasis and from localized cancer, respectively) and RWPE1 cells derived from normal prostate epithelium. Cells were treated with hydrogen peroxide (H2O2) and PC3 cells were also treated with diethyl maleate (DEM). The effect on cell growth, viability, mitochondria membrane potential and oxidative stress was analysed. Oxidative stress was evaluated based on ROS production, oxidative lesion of lipids (MDA) and on determination of antioxidants, including enzyme activity of glutathione peroxidase (Gl-Px), glutathione reductase (Gl-Red) and on the quantification of glutathione (GSH), glutathione-s-transferase (GST) and total antioxidant status (TAS). PC3 shows higher ROS production but also the highest GSH levels and Gl-Red activity, possibly contributing to oxidative stress resistance. This is also associated with higher mitochondrial membrane potential, TAS and lower lipid peroxidation. On the other hand, we identified Gl-Red activity reduction as a new strategy in overcoming oxidative stress resistance, by inducing H2O2 cytotoxicity. Therefore these results suggest Gl-Red activity reduction as a new potential therapeutic approach, in prostate cancer.
authors: General Pathology Laboratory, Faculty of Medicine, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal ; CIMAGO - Centre of Investigation in Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Apartado, 9015 3001-301 Coimbra, Portugal ; CNC - Centre of Neurosciences and Cell Biology, Department of Zoology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors: Mariana
authors: M
authors: Freitas
authors: Inês
authors: I
authors: Baldeiras
authors: Teresa
authors: T
authors: Proença
authors: Vera
authors: V
authors: Alves
authors: Anabela
authors: A
authors: Mota-Pinto
authors: Ana
authors: A
authors: Sarmento-Ribeiro
keywords: Cell line; Glutathione (GSH); Glutathione reductase (Gl-Red); Oxidative stress (OS); Prostate cancer; Reactive oxygen species (ROS)
references: Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11715-20
references: 9751731
references: Biochem Biophys Res Commun. 2011 May 20;408(4):713-9
references: 21549092
references: Free Radic Biol Med. 1989;6(6):631-61
references: 2666278
references: Nutr Cancer. 2007;59(1):8-13
references: 17927496
references: Carcinogenesis. 1997 Jun;18(6):1215-23
references: 9214605
references: Cancer Res. 2008 Mar 15;68(6):1777-85
references: 18339858
references: Clin Cancer Res. 2007 Jul 1;13(13):3796-802
references: 17606710
references: Mol Cell Biol. 2006 Jun;26(12):4701-11
references: 16738333
references: Nat Rev Cancer. 2007 Apr;7(4):256-69
references: 17384581
references: J Natl Cancer Inst. 1995 May 3;87(9):652-61
references: 7752270
references: Biochem Biophys Res Commun. 1993 Nov 30;197(1):40-5
references: 8250945
references: Methods Enzymol. 1990;186:421-31
references: 2233309
references: Methods Enzymol. 1990;186:1-85
references: 2172697
references: Exp Mol Med. 2005 Oct 31;37(5):497-506
references: 16264276
references: Curr Med Chem. 2003 Dec;10(24):2679-92
references: 14529458
references: Clin Chem. 1988 Dec;34(12):2433-8
references: 3197281
references: Prostate. 2000 May 1;43(2):144-9
references: 10754530
references: Cancer. 2000 Jul 1;89(1):123-34
references: 10897009
references: Cell Res. 2004 Feb;14(1):81-5
references: 15040894
references: FASEB J. 1999 Jan;13(1):69-79
references: 9872931
references: Exp Physiol. 1997 Mar;82(2):291-5
references: 9129943
references: J Lab Clin Med. 1967 Jul;70(1):158-69
references: 6066618
references: Biochemistry (Mosc). 2000 Jul;65(7):834-42
references: 10951102
references: J Cell Physiol. 2002 Jul;192(1):1-15
references: 12115731
references: Biochem J. 1990 Feb 1;265(3):659-65
references: 2154966
references: Carcinogenesis. 2004 Aug;25(8):1359-70
references: 15044326
references: Prostate. 1985;6(4):423-36
references: 4088954
references: Cell Physiol Biochem. 2001;11(4):173-86
references: 11509825
references: Gene. 2004 Aug 4;337:1-13
references: 15276197
references: Free Radic Biol Med. 2000 May 1;28(9):1387-404
references: 10924858
references: Lancet. 2003 Mar 8;361(9360):859-64
references: 12642065
references: Carcinogenesis. 2000 Mar;21(3):379-85
references: 10688858
references: Invest Urol. 1979 Jul;17(1):16-23
references: 447482
references: Br Med Bull. 1993 Jul;49(3):523-44
references: 8221020
references: Curr Med Res Opin. 2007 Aug;23(8):1981-6
references: 17631696
references: Int J Cancer. 2004 Jan 1;108(1):130-5
references: 14618627
references: Cancer Res. 1988 Feb 1;48(3):589-601
references: 3335022
references: J Dairy Sci. 1993 Sep;76(9):2812-23
references: 8227685
references: Clin Biochem. 2006 Feb;39(2):176-9
references: 16413012
references: Br J Cancer. 1991 Jun;63(6):963-6
references: 2069852
references: J Urol. 2007 Oct;178(4 Pt 1):1238-43; discussion 1243-4
references: 17698111
references: J Leukoc Biol. 1990 May;47(5):440-8
references: 2159514
references: Cancer Res. 1994 Nov 1;54(21):5579-83
references: 7923200
references: Biochem J. 2000 Jun 1;348 Pt 2:425-32
references: 10816438
references: CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
references: 20610543
references: Free Radic Biol Med. 1995 Apr;18(4):775-94
references: 7750801
references: CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96
references: 18287387
references: Prostate. 1997 Sep 1;32(4):229-33
references: 9288180
references: Science. 1995 Oct 13;270(5234):296-9
references: 7569979
references: Cancer Lett. 2009 Sep 18;282(2):125-36
references: 19185987
references: Cancer. 2001 Nov 1;92(9):2297-308
references: 11745284
references: Prostate. 2000 Jul 1;44(2):144-55
references: 10881024
references: Oncogene. 2005 Jan 6;24(1):77-89
references: 15543233
references: Free Radic Biol Med. 1997;23(1):127-33
references: 9165305
references: Cancer Metastasis Rev. 2002;21(1):3-16
references: 12400993
references: Radiat Res. 1998 Nov;150(5 Suppl):S102-8
references: 9806613
references: Cancer. 2000 May 1;88(9):2092-104
references: 10813721