This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Fan, R. Articles by Bristow, R. G. Search for Related Content PubMed PubMed Citation Articles by Fan, R. Articles by Bristow, R. G.

Defective DNA Strand Break Repair after DNA Damage in Prostate Cancer Cells

Implications for Genetic Instability and Prostate Cancer Progression

¹ Ontario Cancer Institute/Princess Margaret Hospital, University Health Network; and Departments of ² Radiation Oncology, ³ Pathology, and ⁴ Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

Together with cell cycle checkpoint control, DNA repair plays a pivotal role in protecting the genome from endogenous and exogenous DNA damage. Although increased genetic instability has been associated with prostate cancer progression, the relative role of DNA double-strand break repair in malignant versus normal prostate epithelial cells is not known. In this study, we determined the RNA and protein expression of a series of DNA double-strand break repair genes in both normal (PrEC-epithelial and PrSC-stromal) and malignant (LNCaP, DU-145, and PC-3) prostate cultures. Expression of genes downstream of ATM after ionizing radiation-induced DNA damage reflected the p53 status of the cell lines. In the malignant prostate cell lines, mRNA and protein levels of the Rad51, Xrcc3, Rad52, and Rad54 genes involved in homologous recombination were elevated 2- to 5-fold in comparison to normal PrEC cells. The XRCC1, DNA polymerase-ß and - proteins were also elevated. There were no consistent differences in gene expression relating to the nonhomologous end-joining pathway. Despite increased expression of DNA repair genes, malignant prostate cancer cells had defective repair of DNA breaks, alkali-labile sites, and oxidative base damage. Furthermore, after ionizing radiation and mitomycin C treatment, chromosomal aberration assays confirmed that malignant prostate cells had defective DNA repair. This discordance between expression and function of DNA repair genes in malignant prostate cancer cells supports the hypothesis that prostate tumor progression may reflect aberrant DNA repair. Our findings support the development of novel treatment strategies designed to reinstate normal DNA repair in prostate cancer cells.

This article has been cited by other articles:

				A. Choudhury, H. Zhao, F. Jalali, S. AL Rashid, J. Ran, S. Supiot, A. E. Kiltie, and R. G. Bristow Targeting homologous recombination using imatinib results in enhanced tumor cell chemosensitivity and radiosensitivity Mol. Cancer Ther., January 1, 2009; 8(1): 203 - 213. [Abstract] [Full Text] [PDF]

				K. A. Pooley, C. Baynes, K. E. Driver, J. Tyrer, E. M. Azzato, P. D.P. Pharoah, D. F. Easton, B. A.J. Ponder, and A. M. Dunning Common Single-Nucleotide Polymorphisms in DNA Double-Strand Break Repair Genes and Breast Cancer Risk Cancer Epidemiol. Biomarkers Prev., December 1, 2008; 17(12): 3482 - 3489. [Abstract] [Full Text] [PDF]

				J.-Y. Choi, M. L. Neuhouser, M. J. Barnett, C.-C. Hong, A. R. Kristal, M. D. Thornquist, I. B. King, G. E. Goodman, and C. B. Ambrosone Iron intake, oxidative stress-related genes (MnSOD and MPO) and prostate cancer risk in CARET cohort Carcinogenesis, May 1, 2008; 29(5): 964 - 970. [Abstract] [Full Text] [PDF]

				S. Supiot, R. P. Hill, and R. G. Bristow Nutlin-3 radiosensitizes hypoxic prostate cancer cells independent of p53 Mol. Cancer Ther., April 1, 2008; 7(4): 993 - 999. [Abstract] [Full Text] [PDF]

				B. A. Rybicki, C. Neslund-Dudas, C. H. Bock, A. Rundle, A. T. Savera, J. J. Yang, N. L. Nock, and D. Tang Polycyclic Aromatic Hydrocarbon-DNA Adducts in Prostate and Biochemical Recurrence after Prostatectomy Clin. Cancer Res., February 1, 2008; 14(3): 750 - 757. [Abstract] [Full Text] [PDF]

				N. Chan, M. Koritzinsky, H. Zhao, R. Bindra, P. M. Glazer, S. Powell, A. Belmaaza, B. Wouters, and R. G. Bristow Chronic Hypoxia Decreases Synthesis of Homologous Recombination Proteins to Offset Chemoresistance and Radioresistance Cancer Res., January 15, 2008; 68(2): 605 - 614. [Abstract] [Full Text] [PDF]

				H. Huang, K. M. Regan, Z. Lou, J. Chen, and D. J. Tindall CDK2-Dependent Phosphorylation of FOXO1 as an Apoptotic Response to DNA Damage Science, October 13, 2006; 314(5797): 294 - 297. [Abstract] [Full Text] [PDF]

				R. P Singh and R. Agarwal Mechanisms of action of novel agents for prostate cancer chemoprevention. Endocr. Relat. Cancer, September 1, 2006; 13(3): 751 - 778. [Abstract] [Full Text] [PDF]

				N. L. Nock, M. S. Cicek, L. Li, X. Liu, B. A. Rybicki, A. Moreira, S. J. Plummer, G. Casey, and J. S. Witte Polymorphisms in estrogen bioactivation, detoxification and oxidative DNA base excision repair genes and prostate cancer risk Carcinogenesis, September 1, 2006; 27(9): 1842 - 1848. [Abstract] [Full Text] [PDF]

				E. Grlickova-Duzevik, S. S. Wise, R. C. Munroe, W. D. Thompson, and J. P. Wise Sr XRCC1 Protects against Particulate Chromate-Induced Chromosome Damage and Cytotoxicity in Chinese Hamster Ovary Cells Toxicol. Sci., August 1, 2006; 92(2): 409 - 415. [Abstract] [Full Text] [PDF]

				E. Grlickova-Duzevik, S. S. Wise, R. C. Munroe, W. D. Thompson, and J. P. Wise Sr XRCC1 Protects against Particulate Chromate-Induced Chromosome Damage and Cytotoxicity in Chinese Hamster Ovary Cells Toxicol. Sci., July 1, 2006; 92(1): 96 - 102. [Abstract] [Full Text] [PDF]

				S. Vijayakumar, D. C. Hall, X. T. Reveles, D. A. Troyer, I. M. Thompson, D. Garcia, R. Xiang, R. J. Leach, T. L. Johnson-Pais, and S. L. Naylor Detection of Recurrent Copy Number Loss at Yp11.2 Involving TSPY Gene Cluster in Prostate Cancer Using Array-Based Comparative Genomic Hybridization. Cancer Res., April 15, 2006; 66(8): 4055 - 4064. [Abstract] [Full Text] [PDF]

				R. S. Bindra, S. L. Gibson, A. Meng, U. Westermark, M. Jasin, A. J. Pierce, R. G. Bristow, M. K. Classon, and P. M. Glazer Hypoxia-Induced Down-regulation of BRCA1 Expression by E2Fs Cancer Res., December 15, 2005; 65(24): 11597 - 11604. [Abstract] [Full Text] [PDF]

				T. Shiraishi, T. Yoshida, S. Nakata, M. Horinaka, M. Wakada, Y. Mizutani, T. Miki, and T. Sakai Tunicamycin Enhances Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Human Prostate Cancer Cells Cancer Res., July 15, 2005; 65(14): 6364 - 6370. [Abstract] [Full Text] [PDF]

				G. L. Mayeur, W.-J. Kung, A. Martinez, C. Izumiya, D. J. Chen, and H.-J. Kung Ku Is a Novel Transcriptional Recycling Coactivator of the Androgen Receptor in Prostate Cancer Cells J. Biol. Chem., March 18, 2005; 280(11): 10827 - 10833. [Abstract] [Full Text] [PDF]