Editors' ChoiceCancer

Hormones in Repair and Resistance

Sci. Signal.  03 Dec 2013:
Vol. 6, Issue 304, pp. ec293
DOI: 10.1126/scisignal.2004956

The survival of prostate cancer patients receiving radiotherapy is improved by coincident androgen deprivation therapy (ADT). Two laboratories have discovered the molecular basis for this synergy (see Bartek et al.). Through transcriptome analysis of primary human prostate cancer cells treated with an antiandrogen drug (ARN-509), Polkinghorn et al. identified an androgen receptor (AR)–mediated expression profile that included 144 DNA damage response (DDR) genes. Chromatin immunoprecipitation sequencing in LNCaP cells treated with synthetic androgen (R1881) showed that AR bound to 32 DDR genes at a consensus binding site in either their enhancer or promoter regions. Compared with mock-treated cells, androgen-supplemented LNCaP cells had increased DSB repair efficiency and cell survival after ionizing radiation (IR), whereas ARN-509–treated cells showed increased persistence of DSBs even in the absence of IR as well as increased cell death after IR, suggesting that androgen is an important mediator of DSB repair. LNCaP cells treated with ARN-509 showed decreased repair mediated by the DSB repair pathway nonhomologous end joining (NHEJ), similar to that shown by an NHEJ-deficient cell line, whereas it showed no difference in its use of an alternate DSB repair pathway, homologous recombination.

Goodwin et al. first confirmed in culture and in mouse xenografts that ADT or treatment with an AR antagonist (MDV3100) enhanced the antiproliferative and apoptotic effects of radiotherapy on AR-positive, ADT-sensitive LNCaP cells as well as AR-positive but ADT-resistant (also called castration-resistant) C4-2 and 22rv1 cells, mimicking the synergistic effects of combination therapy in humans. IR increased the expression of AR target genes in C4-2 cells, as did doxorubicin (which also induces DSBs) but not ultraviolet light exposure (which primarily induces single-strand DNA breaks). Pretreating cells with the reactive oxygen species (ROS) scavenger N-acetylcysteine prevented the transcriptional effects of IR or doxorubicin on AR target genes, suggesting that AR activation in response to DSBs is mediated at least in part by DNA damage–induced ROS. IR or supplementation with androgen induced the binding of AR to and expression of genes encoding DNA repair enzymes, in particular PRKDC, which encodes DNA-dependent protein kinase catalytic subunit (DNA-PKcs, a critical NHEJ protein). Knocking down DNA-PKcs impaired the ability of C4-2 cells to repair IR-induced DSBs and undergo NHEJ in a plasmid recombination assay. The findings from both laboratories establish that interplay between AR and the NHEJ pathway maintains genome integrity and thus promotes the survival of prostate cancer cells after DNA damage.

J. F. Goodwin, M. J. Schiewer, J. L. Dean, R. S. Schrecengost, R. de Leeuw, S. Han, T. Ma, R. B. Den, A. P. Dicker, F. Y. Feng, K. E. Knudsen, A hormone-DNA repair circuit governs the response to genotoxic insult. Cancer Discov. 3, 1254–1271 (2013). [PubMed]

W. R. Polkinghorn, J. S. Parker, M. X. Lee, E. M. Kass, D. E. Spratt, P. J. Iaquinta, V. K. Arora, W.-F. Yen, L. Cai, D. Zheng, B. S. Carver, Y. Chen, P. A. Watson, N. P. Shah, S. Fujisawa, A. G. Goglia, A. Gopalan, H. Hieronymus, J. Wongvipat, P. T. Scardino, M. J. Zelefsky, M. Jasin, J. Chaudhuri, S. N. Powell, C. L. Sawyers, Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. 3, 1245–1253 (2013). [PubMed]

J. Bartek, M. Mistrik, J. Bartkova, Androgen receptor signaling fuels DNA repair and radioresistance in prostate cancer. Cancer Discov. 3, 1222–1224 (2013). [PubMed]