| Autor: |
Hatem E. Sabaawy, Joseph Bertino, Robert S. DiPaola, Thomas W. Davis, Isaac Y. Kim, Mark N. Stein, John Kerrigan, Daniel Medina, Hua Zhong, Young-Choon Moon, Nadiya Sydorenko, Liangxian Cao, Daniel Jones, Michele Patrizii, Eric Huselid, Kathleen Flaherty, Stephani Davis, Shamila Yusuff, Monica Bartucci, Nitu Bansal |
| Rok vydání: |
2023 |
| Popis: |
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. Clin Cancer Res; 22(24); 6176–91. ©2016 AACR. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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