title: Regulation of prostate cancer cell invasion by modulation of extra- and intracellular redox balance.
abstract: Recent metabolic profiles of human prostate cancer tissues showed a significant increase in cysteine (Cys) and a significant decrease in reduced glutathione (GSH) during cancer progression from low- to high-grade Gleason scores. Cys is primarily localized extracellularly, whereas GSH is present mostly inside the cell. We hypothesized that extra- or intracellular redox state alterations differentially regulate cell invasion in PC3 prostate carcinoma cells versus PrEC normal prostate epithelial cells. Cells were exposed to media with calculated Cys/CySS redox potentials (E(h)CySS) ranging from -60 to -180mV. After 3h exposure to a reducing extracellular redox state (E(h)CySS=-180mV), matrix metalloprotease (MMP), gelatinase, and NADPH oxidase activities increased, correlating with increases in cell invasion, cell migration, and extracellular hydrogen peroxide levels in PC3 cells but not PrECs. Knockdown of NADPH oxidase or MMP with silencing RNAs during cultivation with E(h)CySS=-180mV medium significantly decreased PC3 cell invasion. Modulation of extra- and intracellular redox states by exposure of PC3 cells to Cys/CySS-free medium (approx E(h)CySS=-87mV) containing 500μMN-acetylcysteine resulted in a more reducing intracellular redox state and a significant decrease in cell invasive ability. The decrease in PC3 cell invasion induced by these conditions correlated with a decrease in MMP activity. Our studies demonstrated that an extracellular redox state that was more reducing than a physiologic microenvironment redox state increased PC3 cancer cell invasive ability, whereas an intracellular redox environmental that was more reducing than an intracellular physiologic redox state inhibited PC3 cell invasive ability.
authors: Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
authors: Luksana
authors: L
authors: Chaiswing
authors: Weixiong
authors: W
authors: Zhong
authors: Yongliang
authors: Y
authors: Liang
authors: Dean P
authors: DP
authors: Jones
authors: Terry D
authors: TD
authors: Oberley
mesh_terms: D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000737:chemistry; D003545:Cysteine / Q000737:chemistry / Q000494:pharmacology; D018093:Gelatinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010084:Oxidation-Reduction; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D000975:Antioxidants; D017077:Culture Media, Conditioned; D006861:Hydrogen Peroxide; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; D018093:Gelatinases; D020780:Matrix Metalloproteinase 9; D005978:Glutathione; D003545:Cysteine