Department of Urology, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan.
Prostate. 2012 Sep 15;72(13):1407-11. doi: 10.1002/pros.22492. Epub 2012 Jan 30.
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.
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 (H(2) O(2) ). Cellular apoptosis was quantified by poly (ADP-ribose) polymerase (PARP) cleavage and flow cytometry.
H(2) O(2) induced apoptosis and phosphorylation of ATM, Chk2, and H2AX in LNCaP cells. An ATM inhibitor, Ku55933, reduced H(2) O(2) -induced apoptosis in LNCaP and 22Rv1 cells. Androgen treatments increased H(2) O(2) -induced activation of the DNA damage response and PARP cleavage, but not when the H(2) O(2) -treated cells were also treated with the anti-androgen flutamide. The ATM inhibitor Ku55933 inhibited androgen-induced phosphorylation of ATM and PARP cleavage.
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.
前列腺内持续的慢性炎症和氧化应激会促进前列腺癌的发生。致癌转化过程会导致 DNA 损伤增加，并激活检查点网络，作为阻止癌症进展的诱导性屏障。在这里，我们分析了睾酮对前列腺癌细胞中 DNA 损伤反应的影响，以评估在氧化应激下睾酮是否作为癌症进展的屏障。
我们研究了睾酮对前列腺癌细胞系中 DNA 损伤反应途径成分的影响，包括 ATM（共济失调毛细血管扩张突变激酶）、H2AX（组蛋白 H2AX 变体）和 Chk2（检查点激酶 2），并用不同浓度的过氧化氢（H2O2）处理。通过聚（ADP-核糖）聚合酶（PARP）裂解和流式细胞术定量细胞凋亡。
H2O2 诱导 LNCaP 细胞凋亡和 ATM、Chk2 和 H2AX 的磷酸化。ATM 抑制剂 Ku55933 减少了 LNCaP 和 22Rv1 细胞中 H2O2 诱导的凋亡。雄激素处理增加了 H2O2 诱导的 DNA 损伤反应的激活和 PARP 裂解，但当用抗雄激素氟他胺处理 H2O2 处理的细胞时，这种情况并没有发生。ATM 抑制剂 Ku55933 抑制了雄激素诱导的 ATM 磷酸化和 PARP 裂解。
DNA 损伤反应在应对氧化应激时对维持细胞内稳态起着重要作用。我们的结果表明，在氧化应激下，雄激素信号可能通过激活 DNA 损伤反应诱导细胞凋亡。
