Mithramycin suppresses DNA damage repair via targeting androgen receptor in prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Prostate cancer (PCa) growth relies on androgen receptor (AR) signaling, targeted by current therapies.
• Resistance to treatment arises from aberrant AR expression, mutations, or splice variants.
• Effective strategies against these AR alterations in PCa are needed.

Purpose of the Study:

• To investigate mithramycin (MTM) as a therapeutic agent against AR signaling in PCa.
• To evaluate MTM's effects on AR expression, activity, and DNA damage repair (DDR).

Main Methods:

• Assessed MTM's impact on PCa cell proliferation.
• Analyzed MTM's effects on full-length AR, mutated AR, and AR splice variants.
• Investigated MTM's mechanism on AR genomic targets and enhancers.
• Evaluated MTM's influence on DNA damage repair (DDR) pathways.
• Tested MTM's synergy with ionizing radiation (RT) and bleomycin in PCa models.

Main Results:

• MTM suppressed PCa cell proliferation.
• MTM demonstrated dual inhibition of AR expression and transcriptional activity.
• MTM blocked AR recruitment to genomic targets by occupying AR enhancers.
• MTM downregulated AR target genes, including key DNA repair factors.
• MTM significantly impaired DDR and enhanced the efficacy of RT or bleomycin in PCa.

Conclusions:

• MTM offers a novel therapeutic strategy targeting AR signaling and its variants in PCa.
• MTM's ability to impair DDR and enhance radiation sensitivity presents a promising combination therapy.
• MTM combined with RT or radiomimetic agents could benefit patients with high-risk localized PCa.