Androgen Receptor Contributes to Repairing DNA Damage Induced by Inflammation and Oxidative Stress in Prostate Cancer

Overview

Journal Turk J Biol

Specialty Biology

Date 2023 Dec 29

PMID 38155939

Authors

Bilge Debelec Butuner

Nursah Ertunc Hasbal

Elif Isel

Dirk Roggenbuck

Kemal Sami Korkmaz

Affiliations

Soon will be listed here.

Abstract

Background: Androgen deprivation therapy remains the first-line therapy option for prostate cancer, mostly resulting in the transition of the disease to a castration-resistant state. The lack of androgen signaling during therapy affects various cellular processes, which sometimes paradoxically contributes to cancer progression. As androgen receptor (AR) signaling is known to contribute to oxidative stress regulation, loss of AR may also affect DNA damage level and the response mechanism in oxidant and inflammatory conditions of the prostate tumor microenvironment. Therefore, this study aimed to investigate the role of AR and AR-regulated tumor suppressor upon oxidative stress-induced DNA damage response (DDR) in the inflammatory tumor microenvironment of the prostate.

Materials And Methods: Intracellular reactive oxygen species (ROS) level was induced by either inflammatory conditioned media obtained from lipopolysaccharide-induced macrophages or oxidants and measured by dichlorodihydrofluorescein diacetate. In addition to this, DNA damage was subsequently quantified by counting gH2AX foci using an immunofluorescence-based Aklides platform. Altered expression of proteins function in DDR detected by western blotting.

Results: Cellular levels of ROS and ROS-induced DNA double-strand break damage were analyzed in the absence and presence of AR signaling upon treatment of prostate cancer cells by either oxidants or inflammatory microenvironment exposure. The results showed that AR suppresses intracellular ROS and contributes to DNA damage recognition under oxidant conditions. Besides, increased DNA damage due to loss of NKX3.1 under inflammatory conditions was alleviated by its overexpression. Moreover, the activation of the DDR mediators caused by AR and NKX3.1 activation in androgen-responsive and castration-resistant prostate cancer cells indicated that the androgen receptor function is essential both in controlling oxidative stress and in activating the ROS-induced DDR.

Conclusion: Taken together, it is concluded that the regulatory function of androgen receptor signaling has a vital function in the balance between antioxidant response and DDR activation.

Citing Articles

LncRNA LINC01128 promotes prostate cancer cell proliferation, metastasis, and epithelial-mesenchymal transition by modulating miR-27b-3p.

Zhao Y, Zhang Z, Zheng Y, Bai H, Wu X, Yang Y J Cancer Res Clin Oncol. 2025; 151(3):98.

PMID: 40035871 PMC: 11880183. DOI: 10.1007/s00432-025-06153-6.

References

Bowen C, Ju J, Lee J, Paull T, Gelmann E . Functional activation of ATM by the prostate cancer suppressor NKX3.1. Cell Rep. 2013; 4(3):516-29. PMC: 3838670. DOI: 10.1016/j.celrep.2013.06.039. View

Ushio-Fukai M . Compartmentalization of redox signaling through NADPH oxidase-derived ROS. Antioxid Redox Signal. 2008; 11(6):1289-99. PMC: 2842113. DOI: 10.1089/ars.2008.2333. View

Teramoto S, Tomita T, Matsui H, Ohga E, Matsuse T, Ouchi Y . Hydrogen peroxide-induced apoptosis and necrosis in human lung fibroblasts: protective roles of glutathione. Jpn J Pharmacol. 1999; 79(1):33-40. DOI: 10.1254/jjp.79.33. View

Klein E, Silverman R . Inflammation, infection, and prostate cancer. Curr Opin Urol. 2008; 18(3):315-9. DOI: 10.1097/MOU.0b013e3282f9b3b7. View

Khalili M, Mutton L, Gurel B, Hicks J, De Marzo A, Bieberich C . Loss of Nkx3.1 expression in bacterial prostatitis: a potential link between inflammation and neoplasia. Am J Pathol. 2010; 176(5):2259-68. PMC: 2861091. DOI: 10.2353/ajpath.2010.080747. View

Bowen C, Zheng T, Gelmann E . NKX3.1 Suppresses TMPRSS2-ERG Gene Rearrangement and Mediates Repair of Androgen Receptor-Induced DNA Damage. Cancer Res. 2015; 75(13):2686-98. PMC: 4511965. DOI: 10.1158/0008-5472.CAN-14-3387. View

Liu B, Chen Y, St Clair D . ROS and p53: a versatile partnership. Free Radic Biol Med. 2008; 44(8):1529-35. PMC: 2359898. DOI: 10.1016/j.freeradbiomed.2008.01.011. View

Tam N, Gao Y, Leung Y, Ho S . Androgenic regulation of oxidative stress in the rat prostate: involvement of NAD(P)H oxidases and antioxidant defense machinery during prostatic involution and regrowth. Am J Pathol. 2003; 163(6):2513-22. PMC: 1892368. DOI: 10.1016/S0002-9440(10)63606-1. View

Finkel T . Oxidant signals and oxidative stress. Curr Opin Cell Biol. 2003; 15(2):247-54. DOI: 10.1016/s0955-0674(03)00002-4. View

10.

Debelec-Butuner B, Ertunc N, Korkmaz K . Inflammation contributes to NKX3.1 loss and augments DNA damage but does not alter the DNA damage response via increased SIRT1 expression. J Inflamm (Lond). 2015; 12:12. PMC: 4336697. DOI: 10.1186/s12950-015-0057-4. View

11.

De Marzo A, Platz E, Sutcliffe S, Xu J, Gronberg H, Drake C . Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007; 7(4):256-69. PMC: 3552388. DOI: 10.1038/nrc2090. View

12.

Bowen C, Bubendorf L, Voeller H, Slack R, Willi N, Sauter G . Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. Cancer Res. 2000; 60(21):6111-5. View

13.

Davey R, Grossmann M . Androgen Receptor Structure, Function and Biology: From Bench to Bedside. Clin Biochem Rev. 2016; 37(1):3-15. PMC: 4810760. View

14.

Reddig A, Lorenz S, Hiemann R, Guttek K, Hartig R, Heiserich L . Assessment of modulated cytostatic drug resistance by automated γH2AX analysis. Cytometry A. 2015; 87(8):724-32. DOI: 10.1002/cyto.a.22667. View

15.

Karanika S, Karantanos T, Li L, Corn P, Thompson T . DNA damage response and prostate cancer: defects, regulation and therapeutic implications. Oncogene. 2014; 34(22):2815-22. PMC: 4333141. DOI: 10.1038/onc.2014.238. View

16.

Takeda M, Shirato I, Kobayashi M, Endou H . Hydrogen peroxide induces necrosis, apoptosis, oncosis and apoptotic oncosis of mouse terminal proximal straight tubule cells. Nephron. 1999; 81(2):234-8. DOI: 10.1159/000045282. View

17.

Morgan M, Liu Z . Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res. 2010; 21(1):103-15. PMC: 3193400. DOI: 10.1038/cr.2010.178. View

18.

Markowski M, Bowen C, Gelmann E . Inflammatory cytokines induce phosphorylation and ubiquitination of prostate suppressor protein NKX3.1. Cancer Res. 2008; 68(17):6896-901. PMC: 2586101. DOI: 10.1158/0008-5472.CAN-08-0578. View

19.

Yuan H, Zhang W, Du Y, Hu F . Ternary nanoparticles of anionic lipid nanoparticles/protamine/DNA for gene delivery. Int J Pharm. 2010; 392(1-2):224-31. DOI: 10.1016/j.ijpharm.2010.03.025. View

20.

Reddig A, Voss L, Guttek K, Roggenbuck D, Feist E, Reinhold D . Impact of Different JAK Inhibitors and Methotrexate on Lymphocyte Proliferation and DNA Damage. J Clin Med. 2021; 10(7). PMC: 8036268. DOI: 10.3390/jcm10071431. View