Human prx1 Gene Is a Target of Nrf2 and Is Up-regulated by Hypoxia/Reoxygenation: Implication to Tumor Biology

Abstract

Peroxiredoxin 1 (Prx1) has been found to be elevated in several human cancers. The cell survival-enhancing function of Prx1 is traditionally attributed to its reactive oxygen species-removing capacity, although the growth-promoting role of Prx1 independent of this antioxidant activity is increasingly gaining attention. Although much progress has been made in understanding the behavior of Prx1, little information is available on the mechanism responsible for the abnormal elevation of Prx1 level in cancer. We hypothesized that the hypoxic and unstable oxygenation microenvironment of a tumor might be crucial for prx1 up-regulation. In this study, we cloned the human prx1 promoter and identified nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) as a key transcription factor. Hypoxia/reoxygenation, an in vitro condition suited to mimic changes of oxygenation, increased Nrf2 nuclear localization and its binding to the electrophileresponsive elements located at the proximal (À536 to À528) and distal (À1429 to À1421) regions of the prx1 promoter. A significant reduction of both steady-state and hypoxia/ reoxygenation-mediated prx1 gene expression was shown in Nrf2 knock-out cells. Our results indicated that decreased Kelch-like ECH-associated protein, Keap1, might be an important mechanism for the increased nuclear translocation and activation of Nrf2 in response to hypoxia/reoxygenation. A constitutive elevation of prx1 mRNA and protein was observed in Keap1 knock-out cells. The above information suggests that the Nrf2-Prx1 axis may be a fruitful target for intervention with respect to inhibiting the malignant progression and/or reducing the treatment resistance of cancer cells.

Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy

“…Although constitutive expression in a tumorigenic situation could be devastating because it could provide a survival advantage to invasive and metastatic cancer cells, such as the adaptation to microenvironment and the evolvement of chemoresistance in cancer cells that are known to occur in tumor hypoxia (38,39). In addition, cross-talk between tumor hypoxia and induction of Nrf2 has also been suggested recently (40). It is also noteworthy that inhibition of the Nrf2 pathway in these cancer cells enhanced sensitivity to the anti-cancer reagent cisplatin.…”

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

“…Phosphorylation of PrxI and II by cdc2/cyclin B complexes regulates oligomeric transitions and peroxidase activity, providing yet another mechanism to control the activity and structural state of these enzymes during the cell cycle. Changes in Prx mRNA and protein expression levels occur in many disease states, including cancer [74][75][76][77], suggesting that control of Prx function is regulated at both transcriptional and post-translational levels. While these observations show that the biological functions of individual Prxs exceed the mere reduction of H 2 O 2 , additional investigation is needed to define the array of protein complexes that include Prxs in mammalian cells, and to understand how changes in oxidation state and structural transitions of Prxs contribute to signal transduction in specific regulatory networks.…”

An Auto-regulatory Loop between Stress Sensors INrf2 and Nrf2 Controls Their Cellular Abundance

“…The ARE was first identified as cis-element in the upstream regulatory region of the GSTA2 gene (5) and was found in the promoters of detoxifying enzyme genes such as glutathione S-transferases (6), NAD(P)H:quinone oxidoreductases (NQOs) (7,8), gastrointestinal glutathione peroxidase (9), and peroxiredoxin1 (10). The ARE is recognized by a subset of Cap'n'Collarcontaining basic leucine zipper proteins, nuclear factor erythroid 2-related factors (Nrfs), including Nrf1, Nrf2, and Nrf3.…”