Testosterone promotes DNA damage response under oxidative stress in prostate cancer cell lines

• Published in: The Prostate Vol. 72; no. 13; pp. 1407 - 1411
• Main Authors: Ide, Hisamitsu, Lu, Yan, Yu, Jingsong, China, Toshiyuki, Kumamoto, Tomoka, Koseki, Tatsuro, Yamaguchi, Raizo, Muto, Satoru, Horie, Shigeo
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.09.2012; Wiley-Liss
• Subjects: androgen receptor; Apoptosis - drug effects; Apoptosis - genetics; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Checkpoint Kinase 2; DNA Damage - drug effects; DNA Damage - genetics; DNA damage response; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gynecology. Andrology. Obstetrics; Histones - genetics; Histones - metabolism; Humans; Hydrogen Peroxide - pharmacology; Male; Male genital diseases; Medical sciences; Nephrology. Urinary tract diseases; oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; Phosphorylation - drug effects; Prostate - drug effects; Prostate - metabolism; Prostate - pathology; prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; testosterone; Testosterone - pharmacology; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Andrology; Oxidative stress; Nephrology; Urinary system disease; Androgen; Prostate disease; DNA damage response; Gynecology; Malignant tumor; Testosterone; Cell line; Established cell line; Androgen receptor; Testicular hormone; Sex steroid hormone; Male genital diseases; Prostate cancer; Tumor cell; Cancer; Hormonal receptor
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.22492

BACKGROUND Sustained chronic inflammation and oxidative stress in the prostate promote prostate carcinogenesis. The process of oncogenic transformation leads to enhanced DNA damage and activates the checkpoint network that functions as an inducible barrier against cancer progression. Here, we analyzed the effects of testosterone on the DNA damage response in prostate cancer cells to assess whether testosterone functions a barrier to cancer progression under the oxidative stress. METHODS We examined the effects of testosterone on components of the DNA damage response pathway, including ATM (ataxia‐telangiectasia‐mutated kinase), H2AX (histone H2AX variant), and Chk2 (checkpoint kinase2) in prostate cancer cell lines, treated with various concentration of hydrogen peroxide (H2O2). Cellular apoptosis was quantified by poly (ADP‐ribose) polymerase (PARP) cleavage and flow cytometry. RESULTS H2O2 induced apoptosis and phosphorylation of ATM, Chk2, and H2AX in LNCaP cells. An ATM inhibitor, Ku55933, reduced H2O2‐induced apoptosis in LNCaP and 22Rv1 cells. Androgen treatments increased H2O2‐induced activation of the DNA damage response and PARP cleavage, but not when the H2O2‐treated cells were also treated with the anti‐androgen flutamide. The ATM inhibitor Ku55933 inhibited androgen‐induced phosphorylation of ATM and PARP cleavage. CONCLUSIONS DNA damage responses play important roles in the maintenance of the cell homeostasis in response to oxidative stress. Our results indicated that under oxidative stress androgen signaling may induce apoptosis by activating the DNA damage response. Prostate 72:1407–1411, 2012. © 2012 Wiley Periodicals, Inc.