Mithramycin suppresses DNA damage repair via targeting androgen receptor in prostate cancer. (28th September 2020)

• Record Type: Journal Article
• Authors: Wang, Shan; Gilbreath, Collin; Kollipara, Rahul K.; Sonavane, Rajni; Huo, Xiaofang; Yenerall, Paul; Das, Amit; Ma, Shihong; Raj, Ganesh V.; Kittler, Ralf
• Is Part Of: Cancer letters. Volume 488(2020)
• Page Start: 40
• Page End: 49
• Publication Date: 2020-09-28
• Subjects: Mithramycin -- Androgen receptor -- DNA damage Repair -- Ionizing radiation -- Bleomycin; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.05.027
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The dependency of prostate cancer (PCa) growth on androgen receptor (AR) signaling has been harnessed to develop first-line therapies for high-risk localized and metastatic PCa treatment. However, the occurrence of aberrant expression, mutated or splice variants of AR confers resistance to androgen ablation therapy (ADT), radiotherapy or chemotherapy in AR-positive PCa. Therapeutic strategies that effectively inhibit the expression and/or transcriptional activity of full-length AR, mutated AR and AR splice variants have remained elusive. In this study, we report that mithramycin (MTM), an antineoplastic antibiotic, suppresses cell proliferation and exhibits dual inhibitory effects on expression and transcriptional activity of AR and AR splice variants. MTM blocks AR recruitment to its genomic targets by occupying AR enhancers and causes downregulation of AR target genes, which includes key DNA repair factors in DNA damage repair (DDR). We show that MTM significantly impairs DDR and enhances the effectiveness of ionizing radiation or the radiomimetic agent Bleomycin in PCa. Thus, the combination of MTM treatment with RT or radiomimetic agents, such as bleomycin, may present a novel effective therapeutic strategy for patients with high-risk, clinically localized PCa. Highlights: Mithramycin inhibits the expression of AR and AR splice variants. Mithramycin blocks the transcriptional activity of AR and AR splice variants. Mithramycin attenuates the ability of DNA damage repair in PCa cells. MTM has synergistic therapeutic potential with ionizing radiation or the radiomimetic agent Bleomycin in PCa.