This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ouyang, X. Articles by Abate-Shen, C. Search for Related Content PubMed PubMed Citation Articles by Ouyang, X. Articles by Abate-Shen, C.

Loss-of-Function of Nkx3.1 Promotes Increased Oxidative Damage in Prostate Carcinogenesis

¹ Center for Advanced Biotechnology and Medicine, ² The Cancer Institute of New Jersey, Departments of ³ Medicine and ⁴ Neuroscience, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey; Departments of ⁵ Radiation Oncology and Molecular Radiation Sciences, ⁶ Urology, and ⁷ Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Cory Abate-Shen, University of Medicine and Dentistry of New Jersey-Center for Advanced Biotechnology and Medicine, Robert Wood Johnson Medical School, 679 Hoes Lane, Piscataway, NJ 08854-5638. Phone: 732-235-5161; Fax: 732-235-5789; E-mail: abate{at}cabm.rutgers.edu.

Despite the significance of oxidative damage for carcinogenesis, the molecular mechanisms that lead to increased susceptibility of tissues to oxidative stress are not well-understood. We now report a link between loss of protection against oxidative damage and loss-of-function of Nkx3.1, a homeobox gene that is known to be required for prostatic epithelial differentiation and suppression of prostate cancer. Using gene expression profiling, we find that Nkx3.1 mutant mice display deregulated expression of several antioxidant and prooxidant enzymes, including glutathione peroxidase 2 and 3 (GPx2 and GPx3), peroxiredoxin 6 (Prdx6), and sulfyhydryl oxidase Q6 (Qscn6). Moreover, the formation of prostatic intraepithelial neoplasia in these mutant mice is associated with increased oxidative damage of DNA, as evident by increased levels of 8-hydroxy-2'-deoxyguanosine. We further show that progression to prostate adenocarcinoma, as occurs in compound mutant mice lacking Nkx3.1 as well as the Pten tumor suppressor, is correlated with a further deregulation of antioxidants, including superoxide dismutase enzymes, and more profound accumulations of oxidative damage to DNA and protein, the latter manifested by increased levels of 4-hydroxynonenal. We propose that the essential role of Nkx3.1 in maintaining the terminally differentiated state of the prostate epithelium provides protection against oxidative damage and, thereby, suppression of prostate cancer. Thus, our findings provide a molecular link between a gene whose inactivation is known to be involved in prostate carcinogenesis, namely Nkx3.1, and oxidative damage of the prostatic epithelium.

This article has been cited by other articles:

				A. N. Malhas, C. F. Lee, and D. J. Vaux Lamin B1 controls oxidative stress responses via Oct-1 J. Cell Biol., January 12, 2009; 184(1): 45 - 55. [Abstract] [Full Text] [PDF]

				L. Guo, D. Zhong, S. Lau, X. Liu, X.-Y. Dong, X. Sun, V. W. Yang, P. M. Vertino, C. S. Moreno, V. Varma, et al. Sox7 Is an Independent Checkpoint for {beta}-Catenin Function in Prostate and Colon Epithelial Cells Mol. Cancer Res., September 1, 2008; 6(9): 1421 - 1430. [Abstract] [Full Text] [PDF]

				A. Naiki-Ito, M. Asamoto, N. Hokaiwado, S. Takahashi, H. Yamashita, H. Tsuda, K. Ogawa, and T. Shirai Gpx2 Is an Overexpressed Gene in Rat Breast Cancers Induced by Three Different Chemical Carcinogens Cancer Res., December 1, 2007; 67(23): 11353 - 11358. [Abstract] [Full Text] [PDF]

				Y. P. Yu, G. Yu, G. Tseng, K. Cieply, J. Nelson, M. Defrances, R. Zarnegar, G. Michalopoulos, and J.-H. Luo Glutathione Peroxidase 3, Deleted or Methylated in Prostate Cancer, Suppresses Prostate Cancer Growth and Metastasis Cancer Res., September 1, 2007; 67(17): 8043 - 8050. [Abstract] [Full Text] [PDF]

				C. R. Bethel, D. Faith, X. Li, B. Guan, J. L. Hicks, F. Lan, R. B. Jenkins, C. J. Bieberich, and A. M. De Marzo Decreased NKX3.1 Protein Expression in Focal Prostatic Atrophy, Prostatic Intraepithelial Neoplasia, and Adenocarcinoma: Association with Gleason Score and Chromosome 8p Deletion. Cancer Res., November 15, 2006; 66(22): 10683 - 10690. [Abstract] [Full Text] [PDF]

				C. A. Casiano, M. Mediavilla-Varela, and E. M. Tan Tumor-associated Antigen Arrays for the Serological Diagnosis of Cancer Mol. Cell. Proteomics, October 1, 2006; 5(10): 1745 - 1759. [Abstract] [Full Text] [PDF]

				G. J. Kelloff, S. M. Lippman, A. J. Dannenberg, C. C. Sigman, H. L. Pearce, B. J. Reid, E. Szabo, V. C. Jordan, M. R. Spitz, G. B. Mills, et al. Progress in Chemoprevention Drug Development: The Promise of Molecular Biomarkers for Prevention of Intraepithelial Neoplasia and Cancer--A Plan to Move Forward Clin. Cancer Res., June 15, 2006; 12(12): 3661 - 3697. [Abstract] [Full Text] [PDF]