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Cell, Tumor, and Stem Cell Biology |
Departments of 1 Cell Stress Biology and 2 Cancer Prevention, Roswell Park Cancer Institute, Buffalo, New York and 3 Department of Biological Sciences, Chonnam National University, Kwangju, Korea
Requests for reprints: Young-Mee Park, Department of Cell Stress Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-3190; Fax: 716-845-8899; E-mail: young-mee.park{at}roswellpark.org.
Radiotherapy is one of the major treatment modalities for lung cancer. Cell killing by ionizing radiation is mediated primarily through the reactive oxygen species (ROS) and ROS-driven oxidative stress. Prx1, a peroxiredoxin family member, was shown to be frequently elevated in lung cancer cells and tissues. Although the antioxidant function of Prx1 is expected to affect the radiotherapy response of lung cancer, the physiologic significance of its peroxidase activity in irradiated cells is unclear because the catalytic Cys52 is easily inactivated by ROS due to its overoxidation to sulfinic or sulfonic acid. In this study, we investigated the role of Prx1 in radiation sensitivity of human lung cancer cells, with special emphasis on the redox status of the catalytic Cys52. We found that overexpression of Prx1 enhances the clonogenic survival of irradiated cells and suppresses ionizing radiation–induced c-Jun NH2-terminal kinase (JNK) activation and apoptosis. The peroxidase activity of Prx1, however, is not essential for inhibiting JNK activation. The latter effect is mediated through its association with the glutathione S-transferase pi (GSTpi)-JNK complex, thereby preventing JNK release from the complex. Reduced JNK activation is observed when the peroxidase activity of Prx1 is compromised by Cys52 overoxidation or in the presence of the Cys52 to Ser52 mutant (Prx1C52S) lacking peroxidase activity. We show that both Prx1 and Prx1C52S interact with the GSTpi-JNK complex and suppress the release of JNK from the complex. Our study provides new insight into the antiapoptotic function of Prx1 in modulating radiosensitivity and provides the impetus to monitor the influence of Prx1 levels in the management of lung cancer. (Cancer Res 2006; 66(14): 7136-42)
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 Y. M. Lee, S. H. Park, D.-I. Shin, J.-Y. Hwang, B. Park, Y.-J. Park, T. H. Lee, H. Z. Chae, B. K. Jin, T. H. Oh, et al. Oxidative Modification of Peroxiredoxin Is Associated with Drug-induced Apoptotic Signaling in Experimental Models of Parkinson Disease J. Biol. Chem., April 11, 2008; 283(15): 9986 - 9998. [Abstract] [Full Text] [PDF]
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 I. Iraqui, G. Faye, S. Ragu, A. Masurel-Heneman, R. D. Kolodner, and M.-E. Huang Human Peroxiredoxin PrxI Is an Orthologue of Yeast Tsa1, Capable of Suppressing Genome Instability in Saccharomyces cerevisiae Cancer Res., February 15, 2008; 68(4): 1055 - 1063. [Abstract] [Full Text] [PDF]
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 D. M. Townsend S-Glutathionylation: Indicator of Cell Stress and Regulator of the Unfolded Protein Response Mol. Interv., December 1, 2007; 7(6): 313 - 324. [Abstract] [Full Text] [PDF]
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S. L. Holley, A. A. Fryer, J. W. Haycock, S. E.W. Grubb, R. C. Strange, and P. R. Hoban Differential effects of glutathione S-transferase pi (GSTP1) haplotypes on cell proliferation and apoptosis Carcinogenesis, November 1, 2007; 28(11): 2268 - 2273. [Abstract] [Full Text] [PDF]
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S.-Y. Park, X. Yu, C. Ip, J. L. Mohler, P. N. Bogner, and Y.-M. Park Peroxiredoxin 1 Interacts with Androgen Receptor and Enhances Its Transactivation Cancer Res., October 1, 2007; 67(19): 9294 - 9303. [Abstract] [Full Text] [PDF]
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W. Lee, K.-S. Choi, J. Riddell, C. Ip, D. Ghosh, J.-H. Park, and Y.-M. Park Human Peroxiredoxin 1 and 2 Are Not Duplicate Proteins: THE UNIQUE PRESENCE OF CYS83 IN Prx1 UNDERSCORES THE STRUCTURAL AND FUNCTIONAL DIFFERENCES BETWEEN Prx1 AND Prx2 J. Biol. Chem., July 27, 2007; 282(30): 22011 - 22022. [Abstract] [Full Text] [PDF]
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J.-H. Kim, P. N. Bogner, N. Ramnath, Y. Park, J. Yu, and Y.-M. Park Elevated Peroxiredoxin 1, but not NF-E2-Related Factor 2, Is an Independent Prognostic Factor for Disease Recurrence and Reduced Survival in Stage I Non-Small Cell Lung Cancer Clin. Cancer Res., July 1, 2007; 13(13): 3875 - 3882. [Abstract] [Full Text] [PDF]
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Y.-J. Kim, J.-Y. Ahn, P. Liang, C. Ip, Y. Zhang, and Y.-M. Park Human prx1 Gene Is a Target of Nrf2 and Is Up-regulated by Hypoxia/Reoxygenation: Implication to Tumor Biology Cancer Res., January 15, 2007; 67(2): 546 - 554. [Abstract] [Full Text] [PDF]
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