Inhibition of base excision repair by natamycin suppresses prostate cancer cell proliferation

Authors

Judy L. Vasquez, Department of Human and Molecular Genetics, Florida International University, Herbert Wertheim College of Medicine
Yanhao Lai, Biomolecular Sciences Institute and Department of Chemistry and Biochemistry, Florida International University
Thirunavukkarasu Annamalai, Biomolecular Sciences Institute and Department of Chemistry and Biochemistry, Florida International University
Zhongliang Jiang, Biochemistry Ph.D. Program, Florida International University
Manqi Zhang, Biochemistry Ph.D. Program, Florida International University
Ruipeng Lei, Biochemistry Ph.D. Program, Florida International University
Zunzhen Zhang, Sichuan University West China School of Public Health
Yuan Liu, Department of Chemistry and Biochemistry and Biomolecular Sciences Institute, Florida International University
Yuk-Ching Tse-Dinh, Department of Chemistry and Biochemistry and Biomolecular Sciences Institute, Florida International University
Irina U. Agoulnik, Department of Human and Molecular Genetics, Florida International University, Herbert Wertheim College of Medicine; Department of Chemistry and Biochemistry and Biomolecular Sciences Institute, Florida International University

Date of this Version

1-1-2020

Document Type

Article

Rights

default

Abstract

Prostate cancer (PCa) progression is characterized by increased expression and transcriptional activity of the androgen receptor (AR). In the advanced stages of prostate cancer, AR significantly upregulates the expression of genes involved in DNA repair. Upregulation of expression for base excision repair (BER) related genes is associated with poor patient survival. Thus, inhibition of the BER pathway may prove to be an effective therapy for prostate cancer. Using a high throughput BER capacity screening assay, we sought to identify BER inhibitors that can synergize with castration therapy. An FDA-approved drug library was screened to identify inhibitors of BER using a fluorescence-based assay suitable for HTS. A gel-based secondary assay confirmed the reduction of BER capacity by compounds identified in the primary screen. Five compounds were then selected for further testing in the independently derived, androgen-dependent prostate cancer cell lines, LNCaP and LAPC4, and in the nonmalignant prostate derived cell lines PNT1A and RWPE1. Further analysis led to the identification of a lead compound, natamycin, as an effective inhibitor of key BER enzymes DNA polymerase β (pol β) and DNA Ligase I (LIG I). Natamycin significantly inhibited proliferation of PCa cells in an androgen depleted environment at 1 μM concentration, however, growth inhibition did not occur with nonmalignant prostate cell lines, suggesting that BER inhibition may improve efficacy of the castration therapies.

DOI

10.1016/j.biochi.2019.11.008

Identifier

31756402

Comments

Pubmed Accepted Manuscript

Recommended Citation

Vasquez JL, Lai Y, Annamalai T, Jiang Z, Zhang M, Lei R, Zhang Z, Liu Y, Tse-Dinh YC, Agoulnik IU. Inhibition of base excision repair by natamycin suppresses prostate cancer cell proliferation. Biochimie. 2020 Jan;168:241-250. doi: 10.1016/j.biochi.2019.11.008. Epub 2019 Nov 19. PMID: 31756402; PMCID: PMC6926147.