BMI-1 targeting interferes with patient-derived tumor-initiating cell survival and tumor growth in prostate cancer

Nitu Bansal, Monica Bartucci, Shamila Yusuff, Stephani Davis, Kathleen Flaherty, Eric Huselid, Michele Patrizii, Daniel Jones, Liangxian Cao, Nadiya Sydorenko, Young Choon Moon, Hua Zhong, Daniel Medina, John Kerrigan, Mark N. Stein, Isaac Y. Kim, Thomas W. Davis, Robert S. DiPaola, Joseph Bertino, Hatem E. Sabaawy

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Purpose: Current prostate cancer management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TIC-tailored therapies appears to be a promising approach. Experimental Design: We have previously developed a combined immunophenotypic and time-of-adherence assay to identify CD49bhiCD29hiCD44hi cells as human prostate TICs. We utilized this assay with patient-derived prostate cancer cells and xenograft models to characterize the effects of pharmacologic inhibitors of BMI-1. Results: We demonstrate that in cell lines and patient-derived TICs, BMI-1 expression is upregulated and associated with stem cell-like traits. From a screened library, we identified a number of post-transcriptional small molecules that target BMI-1 in prostate TICs. Pharmacologic inhibition of BMI-1 in patient-derived cells significantly decreased colony formation in vitro and attenuated tumor initiation in vivo, thereby functionally diminishing the frequency of TICs, particularly in cells resistant to proliferation- and androgen receptor-directed therapies, without toxic effects on normal tissues. Conclusions: Our data offer a paradigm for targeting TICs and support the development of BMI-1-targeting therapy for a more effective prostate cancer treatment.

Original languageEnglish (US)
Pages (from-to)6176-6191
Number of pages16
JournalClinical Cancer Research
Volume22
Issue number24
DOIs
StatePublished - Dec 15 2016

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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