J. Cancer Mol. 3: 37-43, 2007

[Review Article]

Targeting the Nrf2-Prx1 Pathway with Selenium to Enhance the Efficacy and Selectivity of Cancer Therapy

Yun-Jeong Kim, Sun-Hee Baek, Paul N. Bogner, Clement Ip, Youcef M. Rustum, Marwan G. Fakih, Nithya Ramnath, and Young-Mee Park¹

Departments of Cell Stress Biology [Y.-J. Kim, S.-H. Baek, Y.-M. Park], Pathology [P. N. Bogner], Cancer Chemoprevention [C. Ip], Pharmacology [Y. M. Rustum], and Medicine [M. G. Fakih, N. Ramnath], Roswell Park Cancer Institute, Buffalo, NY, USA

Abstract:

Peroxiredoxin 1 (Prx1) is frequently elevated in human cancer.  Although the cell survival enhancing function of Prx1 has traditionally been attributed to its antioxidant activity, the growth promoting role of Prx1 independent of its antioxidant activity is increasingly gaining attention.  Prx1 interacts with and modulates the activities of growth regulatory proteins in a fashion favoring cell survival.  The human prx1 promoter was recently cloned and characterized.  It was found that hypoxia/reoxygenation, an in vitro condition mimicking unstable oxygenation of a tumor, up-regulates prx1 through the activation of NF-E2-related factor 2, also known as Nrf2.  Studies have shown that a Nrf2 suppressor Keap1 is often mutated in cancer cells resulting in a constitutive activation of Nrf2.  These findings suggest that both genetic and microenvironmental abnormalities can contribute to the aberrant elevation of prx1 in a subset of cancer cells, conferring on them an aggressive survival phenotype.  Consistent with this hypothesis, elevated expression of Prx1 has been shown to predict disease recurrence and poor clinical outcome, indicating that the Nrf2-Prx1 pathway may prove to be a fruitful new target to inhibit malignant progression and/or reduce treatment resistance.  Recent studies suggest that selenium is a highly effective modulator of various therapeutic agents, and that the anti-cancer activity of selenium may in part be mediated by suppressing the Nrf2-Prx1 pathway of a tumor.  Our current research focus aims at investigating how selenium modulation of the Nrf2-Prx1 pathway may enhance the efficacy and selectivity of cancer therapy in both pre-clinical and clinical settings.

Received 3/12/07; Revised 3/29/07; Accepted 3/30/07.

¹Correspondence: Dr. Young-Mee Park, Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. Phone: 1-716-8453190. Fax: 1-716-8458899. E-mail: young-mee.park@roswellpark.org

²Abbreviations: Prx, peroxiredoxin(s); Nrf2, NF-E2-related factor 2; EpRE/ARE, electrophile or antioxidant responsive element; tBHQ, tert-butylhydroquinone; Keap1, Kelch-like ECH-associated protein 1; Se-Met, seleno-L-methionine; MSC, 5-methylselenocysteine.

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