Effective targeting of RNA polymerase I in treatment-resistant prostate cancer

Jin Yih Low, Paul Sirajuddin, Michael Moubarek, Shreya Agarwal, Apurv Rege, Gunes Guner, Hester Liu, Zhiming Yang, Angelo M. De Marzo, Charles Bieberich, Marikki Laiho

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Abstract

Background: Advanced prostate cancers depend on protein synthesis for continued survival and accelerated rates of metabolism for growth. RNA polymerase I (Pol I) is the enzyme responsible for ribosomal RNA (rRNA) transcription and a rate-limiting step for ribosome biogenesis. We have shown using a specific and sensitive RNA probe for the 45S rRNA precursor that rRNA synthesis is increased in prostate adenocarcinoma compared to nonmalignant epithelium. We have introduced a first-in-class Pol I inhibitor, BMH-21, that targets cancer cells of multiple origins, and holds potential for clinical translation. Methods: The effect of BMH-21 was tested in prostate cancer cell lines and in prostate cancer xenograft and mouse genetic models. Results: We show that BMH-21 inhibits Pol I transcription in metastatic, castration-resistant, and enzalutamide treatment-resistant prostate cancer cell lines. The genetic abrogation of Pol I effectively blocks the growth of prostate cancer cells. Silencing of p53, a pathway activated downstream of Pol I, does not diminish this effect. We find that BMH-21 significantly inhibited tumor growth and reduced the Ki67 proliferation index in an enzalutamide-resistant xenograft tumor model. A decrease in 45S rRNA synthesis demonstrated on-target activity. Furthermore, the Pol I inhibitor significantly inhibited tumor growth and pathology in an aggressive genetically modified Hoxb13-MYC|Hoxb13-Cre|Ptenfl/fl (BMPC) mouse prostate cancer model. Conclusion: Taken together, BMH-21 is a novel promising molecule for the treatment of castration-resistant prostate cancer.

Original languageEnglish (US)
Pages (from-to)1837-1851
Number of pages15
JournalProstate
Volume79
Issue number16
DOIs
StatePublished - Dec 1 2019

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Keywords

  • androgen receptor
  • ribosome biogenesis
  • RNA polymerase I
  • small molecule
  • therapeutics
  • transcription

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

Low, J. Y., Sirajuddin, P., Moubarek, M., Agarwal, S., Rege, A., Guner, G., Liu, H., Yang, Z., De Marzo, A. M., Bieberich, C., & Laiho, M. (2019). Effective targeting of RNA polymerase I in treatment-resistant prostate cancer. Prostate, 79(16), 1837-1851. https://doi.org/10.1002/pros.23909