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

Departments of ¹ Cell Stress Biology, ² Cancer Genetics, and ³ Cancer Chemoprevention, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Young-Mee Park, Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263. Phone: 716-845-3190; Fax: 716-845-8899; E-mail: young-mee.park{at}roswellpark.org.

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 electrophile-responsive elements located at the proximal (–536 to –528) and distal (–1429 to –1421) 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 Res 2007;67(2):546–53]

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