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

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.