Shireen Attaran1,2, John J Skoko1,2, Barbara L Hopkins2,3, Megan K Wright4, Laurel E Wood1, Alparslan Asan1,2, Hyun Ae Woo5, Adam Feinberg6, Carola A Neumann7,8. 1. Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. 2. Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. 3. Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA. 4. University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA. 5. College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea. 6. Department of Materials Science and Engineering and Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. 7. Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. neumannc@upmc.edu. 8. Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. neumannc@upmc.edu.
Abstract
BACKGROUND: Peroxiredoxin 1 (PRDX1) belongs to an abundant family of peroxidases whose role in cancer is still unresolved. While mouse knockout studies demonstrate a tumour suppressive role for PRDX1, in cancer cell xenografts, results denote PRDX1 as a drug target. Probably, this phenotypic discrepancy stems from distinct roles of PRDX1 in certain cell types or stages of tumour progression. METHODS: We demonstrate an important cell-autonomous function for PRDX1 utilising a syngeneic mouse model (BALB/c) and mammary fibroblasts (MFs) obtained from it. RESULTS: Loss of PRDX1 in vivo promotes collagen remodelling known to promote breast cancer progression. PRDX1 inactivation in MFs occurs via SRC-induced phosphorylation of PRDX1 TYR194 and not through the expected direct oxidation of CYS52 in PRDX1 by ROS. TYR194-phosphorylated PRDX1 fails to bind to lysyl oxidases (LOX) and leads to the accumulation of extracellular LOX proteins which supports enhanced collagen remodelling associated with breast cancer progression. CONCLUSIONS: This study reveals a cell type-specific tumour suppressive role for PRDX1 that is supported by survival analyses, depending on PRDX1 protein levels in breast cancer cohorts.
BACKGROUND: Peroxiredoxin 1 (PRDX1) belongs to an abundant family of peroxidases whose role in cancer is still unresolved. While mouse knockout studies demonstrate a tumour suppressive role for PRDX1, in cancer cell xenografts, results denote PRDX1 as a drug target. Probably, this phenotypic discrepancy stems from distinct roles of PRDX1 in certain cell types or stages of tumour progression. METHODS: We demonstrate an important cell-autonomous function for PRDX1 utilising a syngeneic mouse model (BALB/c) and mammary fibroblasts (MFs) obtained from it. RESULTS: Loss of PRDX1 in vivo promotes collagen remodelling known to promote breast cancer progression. PRDX1 inactivation in MFs occurs via SRC-induced phosphorylation of PRDX1 TYR194 and not through the expected direct oxidation of CYS52 in PRDX1 by ROS. TYR194-phosphorylated PRDX1 fails to bind to lysyl oxidases (LOX) and leads to the accumulation of extracellular LOX proteins which supports enhanced collagen remodelling associated with breast cancer progression. CONCLUSIONS: This study reveals a cell type-specific tumour suppressive role for PRDX1 that is supported by survival analyses, depending on PRDX1 protein levels in breast cancer cohorts.
Authors: Manish Mittal; Mohammad Rizwan Siddiqui; Khiem Tran; Sekhar P Reddy; Asrar B Malik Journal: Antioxid Redox Signal Date: 2013-10-22 Impact factor: 8.401
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