Defective DNA strand break repair after DNA damage in prostate cancer cells: Implications for genetic instability and prostate cancer progression

Rong Fan, Tirukalikundram S. Kumaravel, Farid Jalali, Paula Marrano, Jeremy A. Squire, Robert G. Bristow

Research output: Contribution to journalArticlepeer-review

Abstract

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-β and -δ 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.

Original languageEnglish
Pages (from-to)8526-8533
Number of pages8
JournalCancer Research
Volume64
Issue number23
DOIs
Publication statusPublished - 1 Dec 2004

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