Castration-resistant prostate cancer: Androgen receptor inactivation induces telomere DNA damage, and damage response inhibition leads to cell death

Abstract

Telomere stability is important for cell viability, as cells with telomere DNA damage that is not repaired do not survive. We reported previously that androgen receptor (AR) antagonist induces telomere DNA damage in androgen-sensitive LNCaP prostate cancer cells; this triggers a DNA damage response (DDR) at telomeres that includes activation of ATM, and blocking ATM activation prevents telomere DNA repair and leads to cell death. Remarkably, AR antagonist induces telomere DNA damage and triggers ATM activation at telomeres also in 22Rv1 castration-resistant prostate cancer (CRPC) cells that are not growth inhibited by AR antagonist. Treatment with AR antagonist enzalutamide (ENZ) or ATM inhibitor (ATMi) by itself had no effect on growth in vitro or in vivo, but combined treatment with ENZ plus ATMi significantly inhibited cell survival in vitro and tumor growth in vivo. By inducing telomere DNA damage and activating a telomere DDR, an opportunity to inhibit DNA repair and promote cell death was created, even in CRPC cells. 22Rv1 cells express both full-length AR and AR splice variant AR-V7, but full-length AR was found to be the predominant form of AR associated with telomeres and required for telomere stability. Although 22Rv1 growth of untreated 22Rv1 cells appears to be driven by AR-V7, it is, ironically, expression of full-length AR that makes them sensitive to growth inhibition by combined treatment with ENZ plus ATMi. Notably, this combined treatment approach to induce telomere DNA damage and inhibit the DDR was effective in inducing cell death also in other CRPC cell lines (LNCaP/AR and C4-2B). Thus, the use of ENZ in combination with a DDR inhibitor, such as ATMi, may be effective in prolonging disease-free survival of patients with AR-positive metastatic CRPC, even those that co-express AR splice variant.

Androgen Receptor Upregulates Mucosa-Associated Lymphoid Tissue 1 to Induce NF-κB Activity via Androgen-Dependent and -Independent Pathways in Prostate Carcinoma Cells

“…The results of the in vitro cell proliferation and invasion assays showed that the ectopic overexpression of ARv7 enhanced cell proliferation and invasion in both 22Rv1 and PC-3 cells ( Figure 6 ). These results are in agreement with previous studies, which showed the initiation of the growth of 22Rv1 cells by ARv7 [ 10 , 51 ]. Studies have found that high levels of ARv7 are correlated with prostate bone metastasis in vivo, and the epithelial-mesenchymal markers for cell invasion were identified as ARv7 target genes in both LNCaP and 22Rv1 cells in vitro [ 52 , 53 , 54 ].…”

Idarubicin combats abiraterone and enzalutamide resistance in prostate cells via targeting XPA protein

“…Olaparib, a DNA repair inhibitor, in combination with abiraterone, significantly improved the survival of patients with CRPC compared to that observed with abiraterone treatment alone [ 36 ]. Similarly, the combination of ENZ with a DNA repair inhibitor effectively prolonged the survival of patients with CRPC compared to that observed with ENZ alone [ 37 ]. In this study, we found that IDA, in combination with AA, enhanced DNA damage by decreasing XPA protein levels and overcame the resistance of abiraterone and EZN, which is consistent with previous studies [ 36 , 37 ].…”

“…Similarly, the combination of ENZ with a DNA repair inhibitor effectively prolonged the survival of patients with CRPC compared to that observed with ENZ alone [ 37 ]. In this study, we found that IDA, in combination with AA, enhanced DNA damage by decreasing XPA protein levels and overcame the resistance of abiraterone and EZN, which is consistent with previous studies [ 36 , 37 ].…”

Oxidative stress and redox signaling in CRPC progression: therapeutic potential of clinically-tested Nrf2-activators

“…The ataxia-telangiectasia-mutated (ATM) protein is a key regulator of the DNA damage response following oxidative stress. Interestingly, exposure to AR antagonists induces both telomere DNA damage and damage response inhibition in the CRPC cell line 22Rv1 [ 69 ] . Combined exposure to enzalutamide and the ATM inhibitor, KU60019, significantly inhibits cell survival in vitro and tumor growth in vivo [ 69 ] .…”

“…Interestingly, exposure to AR antagonists induces both telomere DNA damage and damage response inhibition in the CRPC cell line 22Rv1 [ 69 ] . Combined exposure to enzalutamide and the ATM inhibitor, KU60019, significantly inhibits cell survival in vitro and tumor growth in vivo [ 69 ] . Most interestingly, our recent in vitro findings [ 70 , 71 ] also showed that coexposure to potent antioxidants, such as the phytochemical sulforaphane [ 70 ] and the synthetic compound, bardoxolone-methyl (CDDO-me) [ 71 ] can also sensitize these 22Rv1 cells to the anti-proliferative effects of enzalutamide.…”