DNA damage signalling barrier, oxidative stress and treatment‐relevant DNA repair factor alterations during progression of human prostate cancer

Molecular Oncology - Tập 10 - Trang 879-894 - 2016
Daniela Kurfurstova1, Jirina Bartkova2,3, Radek Vrtel4,5, Alena Mickova1, Alena Burdova1, Dusana Majera5, Martin Mistrik5, Milan Kral6, Frederic R. Santer7, Jan Bouchal1, Jiri Bartek2,3,5
1Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
2Danish Cancer Society Research Center, Copenhagen, Denmark
3Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
4Department of Medical Genetics, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
5Laboratory of Genome Integrity, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
6Department of Urology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
7Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Austria

Tóm tắt

The DNA damage checkpoints provide an anti‐cancer barrier in diverse tumour types, however this concept has remained unexplored in prostate cancer (CaP). Furthermore, targeting DNA repair defects by PARP1 inhibitors (PARPi) as a cancer treatment strategy is emerging yet requires suitable predictive biomarkers. To address these issues, we performed immunohistochemical analysis of multiple markers of DNA damage signalling, oxidative stress, DNA repair and cell cycle control pathways during progression of human prostate disease from benign hyperplasia, through intraepithelial neoplasia to CaP, complemented by genetic analyses of TMPRSS2‐ERG rearrangement and NQO1, an anti‐oxidant factor and p53 protector. The DNA damage checkpoint barrier (γH2AX, pATM, p53) mechanism was activated during CaP tumorigenesis, albeit less and with delayed culmination compared to other cancers, possibly reflecting lower replication stress (slow proliferation despite cases of Rb loss and cyclin D1 overexpression) and progressive loss of ATM activator NKX3.1. Oxidative stress (8‐oxoguanine lesions) and NQO1 increased during disease progression. NQO1 genotypes of 390 men did not indicate predisposition to CaP, yet loss of NQO1 in CaP suggested potential progression‐opposing tumour suppressor role. TMPRSS2‐ERG rearrangement and PTEN loss, events sensitizing to PARPi, occurred frequently along with heterogeneous loss of DNA repair factors 53BP1, JMJD1C and Rev7 (all studied here for the first time in CaP) whose defects may cause resistance to PARPi. Overall, our results reveal an unorthodox DNA damage checkpoint barrier scenario in CaP tumorigenesis, and provide novel insights into oxidative stress and DNA repair, with implications for biomarker guidance of future targeted therapy of CaP.

Tài liệu tham khảo

10.1074/jbc.M601162200 10.1158/1078-0432.CCR-10-0939 10.1093/jnci/djr500 10.1074/jbc.M211981200 10.1038/nrurol.2011.107 10.1073/pnas.98.3.1188 10.1016/S0955-0674(96)80081-0 Bartek J., 1990, Genetic and immunochemical analysis of mutant p53 in human breast cancer cell lines, Oncogene, 5, 893 10.1038/474171a 10.1038/onc.2010.249 10.1016/j.molonc.2014.07.001 10.1038/nature03482 10.1038/sj.onc.1210553 10.1038/nature05268 10.1073/pnas.93.6.2528 10.1002/pros.21257 10.1038/nsmb.1831 10.1016/j.celrep.2013.06.039 10.1016/j.ccr.2011.04.010 10.1038/nature05327 10.1038/nature09677 10.1016/j.abb.2010.03.019 2004 IARCPress Lyon J.N. Eble G. Sauter J.I. Epstein I.A. Sesterhenn World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs Ergen H.A., 2007, Investigation of NAD(P)H:quinone oxidoreductase 1 (NQO1) C609T polymorphism in prostate cancer, Anticancer Res, 27, 4107 10.1038/cdd.2013.76 10.1038/ng.155 10.1631/jzus.B1300106 10.1038/nature03485 10.1126/science.1140735 10.1038/ncomms8620 10.1016/j.ymeth.2014.01.022 10.1016/0140-6736(90)90801-B 10.1158/0008-5472.CAN-04-3157 10.1158/0008-5472.CAN-10-0937 10.1038/nature08467 10.1038/nature10155 10.1038/nature03097 10.1038/bjc.1997.474 10.1158/1078-0432.CCR-15-0887 10.4149/neo_2014_004 10.1007/s13277-013-1560-y Long D.J., 2000, NAD(P)H:quinone oxidoreductase 1 deficiency increases susceptibility to benzo(a)pyrene-induced mouse skin carcinogenesis, Cancer Res, 60, 5913 10.1038/nature10760 10.1038/ncb2344 Malins D.C., 2001, Age-related radical-induced DNA damage is linked to prostate cancer, Cancer Res, 61, 6025 10.1056/NEJMoa1506859 10.1002/emmm.200900041 10.1097/01.ju.0000116617.32728.ca 10.1158/1541-7786.MCR-13-0672 10.1016/S0140-6736(14)60525-0 10.1111/j.1365-2559.2011.04033.x 10.1016/j.cell.2006.11.042 10.1016/j.matbio.2014.03.001 10.1124/mol.59.2.263 10.1124/mol.52.2.300 10.1124/mol.65.5.1238 10.3322/caac.21208 10.1158/1055-9965.EPI-09-0660 10.1016/S0304-3835(98)00269-9 10.3390/ijms130910959 10.1158/0008-5472.CAN-14-0562 10.1158/0008-5472.CAN-06-2178 10.1038/nsmb.2702 10.1016/j.cancergen.2014.09.003 10.1038/nature14328 10.1126/science.1231573
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Molecular Oncology

Tập 10

879-894

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