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 hCySS) ranging from - 60 to - 180 mV. After 3 h exposure to a reducing extracellular redox state (E hCySS = - 180 mV), 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 hCySS = - 180 mV 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 hCySS = - 87 mV) containing 500 μM N-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.
|Number of pages||10|
|Journal||Free Radical Biology and Medicine|
|State||Published - Jan 15 2012|
Bibliographical noteFunding Information:
The contents do not represent the views of the U.S. Department of Veterans Affairs. This work was supported in part by funds from the University of Wisconsin, Department of Pathology Research and Development Committee, University of Wisconsin–Madison Graduate School, a 2010 minifellowship award from the Society for Free Radical Biology & Medicine and from the National Cancer Institute, University of Wisconsin Carbone Cancer Center (NIH Grant P30 CA014520), NIH Grants RO1 CA07359902 and RO1 CA09485301 (T.D.O.; Co-I), and resources and facilities at the William S. Middleton Memorial Veterans Hospital (Madison, WI, USA). The authors thank Dr. Young-Mi Go, Department of Medicine, Emory University (Atlanta, GA), for technical training of the Trx1 redox Western blot technique.
- Free radicals
- Prostate cancer
ASJC Scopus subject areas
- Physiology (medical)