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

被引:95
作者
Fan, R
Kumaravel, TS
Jalali, F
Marrano, P
Squire, JA
Bristow, RG
机构
[1] UHN, Princess Margaret Hosp, Radiat Med Program, Ontario Canc Inst, Toronto, ON M5G 2M9, Canada
[2] Univ Toronto, Dept Radiat Oncol, Toronto, ON, Canada
[3] Univ Toronto, Dept Pathol, Toronto, ON, Canada
[4] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada
关键词
D O I
10.1158/0008-5472.CAN-04-1601
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 Rad5l, Xrcc3, Rad52, and Rad54 genes involved in homologous recombination were elevated similar to2- to 5-fold in comparison to normal PrEC cells. The XRCC1, DNA polymerase-beta and -delta 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.
引用
收藏
页码:8526 / 8533
页数:8
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