Prdx1 inhibits tumorigenesis via regulating PTEN/AKT activity

Abstract

It is widely accepted that reactive oxygen species (ROS) promote tumorigenesis. However, the exact mechanisms are still unclear. As mice lacking the peroxidase peroxiredoxin1 (Prdx1) produce more cellular ROS and die prematurely of cancer, they offer an ideal model system to study ROS-induced tumorigenesis. Prdx1 ablation increased the susceptibility to Ras-induced breast cancer. We, therefore, investigated the role of Prdx1 in regulating oncogenic Ras effector pathways. We found Akt hyperactive in fibroblasts and mammary epithelial cells lacking Prdx1. Investigating the nature of such elevated Akt activation established a novel role for Prdx1 as a safeguard for the lipid phosphatase activity of PTEN, which is essential for its tumour suppressive function. We found binding of the peroxidase Prdx1 to PTEN essential for protecting PTEN from oxidation-induced inactivation. Along those lines, Prdx1 tumour suppression of Ras-or ErbB-2-induced transformation was mediated mainly via PTEN.

Downregulation of PRDX1 by promoter hypermethylation is frequent in 1p/19q-deleted oligodendroglial tumours and increases radio- and chemosensitivity of Hs683 glioma cells in vitro

“…This may also explain our finding that baseline apoptotic activity in Hs683 glioma cells was slightly elevated after PRDX1 knockdown as compared with control-transduced cells. On the other hand, PRDX1 has been reported to inhibit tumourigenesis by binding the tumour suppressor PTEN and protecting PTEN from oxidation-induced inactivation (Cao et al, 2009). Interestingly, PTEN gene mutations are rare in 1p/19q-deleted and IDH1/2-mutant gliomas but common in primary glioblastomas (Ohgaki and Kleihues, 2009), which in turn usually lack 1p/19q deletion, IDH1 mutation and PRDX1 hypermethylation.…”

“…Prdx1 knockout mice have higher levels of cellular ROS and die prematurely of cancer, indicating a tumour-preventive role of peroxiredoxin 1 (Neumann et al, 2003). More recently, peroxiredoxin 1 has been reported to inhibit tumourigenesis by binding the tumour suppressor PTEN and protecting PTEN from oxidation-induced inactivation (Cao et al, 2009).…”

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…27,55 The peroxidase peroxiredoxin1 (Prdx1) gene product regulates PTEN in response to ROS. 56 In Prdx1-deficient mouse fibroblasts and mammary epithelial cells, Akt is hyperactive. Prdx1 was shown to be essential for the lipid phosphatase activity of PTEN and Prdx1 binding to PTEN is essential for protecting PTEN from oxidation-induced inactivation.…”

Peroxiredoxin 1 Contributes to Host Defenses against Mycobacterium tuberculosis

“…PRDX1-mediated IL-12 production may be regulated by a pathway involving phosphatase and tensin homolog (PTEN) and PI3K, independent of c-Rel induction and p38 MAPK activation. PRDX1 protects PTEN from oxidation-induced inactivation (56). PTEN negatively regulates PI3K signaling (57).…”