Discovery of a Novel Bloom's Syndrome Protein (BLM) Inhibitor Suppressing Growth and Metastasis of Prostate Cancer

Prostate cancer (PCa) is a common cancer and a major cause of cancer-related death worldwide in men, necessitating novel targets for cancer therapy. High expression of Bloom's syndrome protein (BLM) helicase is associated with the occurrence and development of PCa. Therefore, the identification...

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Published inInternational journal of molecular sciences Vol. 23; no. 23; p. 14798
Main Authors Ma, Xiao-Yan, Xu, Hou-Qiang, Zhao, Jia-Fu, Ruan, Yong, Chen, Bin
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 26.11.2022
MDPI
Subjects
Androgens
AO/854
Apoptosis
BLM
Bloom Syndrome - genetics
Bloom Syndrome - metabolism
Bloom's syndrome
Cancer therapies
cell apoptosis
Cell growth
cell proliferation
CHK1 protein
DNA - metabolism
DNA Damage
DNA helicase
Humans
Lymphatic system
Male
Medical prognosis
Metastases
Metastasis
Molecular docking
Molecular Docking Simulation
p53 Protein
Prostate cancer
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - genetics
Protein expression
Proteins
RecQ Helicases - genetics
RecQ Helicases - metabolism
Signal transduction
Therapeutic targets
Tumors
cell apoptosis
BLM
prostate cancer
cell proliferation
AO/854
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Summary:Prostate cancer (PCa) is a common cancer and a major cause of cancer-related death worldwide in men, necessitating novel targets for cancer therapy. High expression of Bloom's syndrome protein (BLM) helicase is associated with the occurrence and development of PCa. Therefore, the identification and development of new BLM inhibitors may be a new direction for the treatment of PCa. Here, we identified a novel inhibitor by molecular docking and put it to systematic evaluation via various experiments, AO/854, which acted as a competitive inhibitor that blocked the BLM-DNA interaction. Cellular evaluation indicated that AO/854-suppressed tumor growth and metastasis in PC3 cells by enhancing DNA damage, phosphorylating Chk1/Chk2, and altering the p53 signaling pathway. Collectively, the study highlights the potential of BLM as a therapeutic target in PCa and reveals a distinct mechanism by which AO/854 competitively inhibits the function of BLM.
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ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms232314798