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HDAC inhibitor confers radiosensitivity to prostate stem-like cells

Frame, F M; Pellacani, D; Collins, A T; Simms, M S; Mann, V M; Jones, GDD; Meuth, M; Bristow, R G; Maitland, N J

Authors

D Pellacani

A T Collins

M S Simms

V M Mann

GDD Jones

M Meuth

R G Bristow

N J Maitland

Abstract

Background:
Radiotherapy can be an effective treatment for prostate cancer, but radiorecurrent tumours do develop. Considering prostate cancer heterogeneity, we hypothesised that primitive stem-like cells may constitute the radiation-resistant fraction.

Methods:
Primary cultures were derived from patients undergoing resection for prostate cancer or benign prostatic hyperplasia. After short-term culture, three populations of cells were sorted, reflecting the prostate epithelial hierarchy, namely stem-like cells (SCs, α2β1integrinhi/CD133+), transit-amplifying (TA, α2β1integrinhi/CD133−) and committed basal (CB, α2β1integrinlo) cells. Radiosensitivity was measured by colony-forming efficiency (CFE) and DNA damage by comet assay and DNA damage foci quantification. Immunofluorescence and flow cytometry were used to measure heterochromatin. The HDAC (histone deacetylase) inhibitor Trichostatin A was used as a radiosensitiser.

Results:
Stem-like cells had increased CFE post irradiation compared with the more differentiated cells (TA and CB). The SC population sustained fewer lethal double-strand breaks than either TA or CB cells, which correlated with SCs being less proliferative and having increased levels of heterochromatin. Finally, treatment with an HDAC inhibitor sensitised the SCs to radiation.

Interpretation:
Prostate SCs are more radioresistant than more differentiated cell populations. We suggest that the primitive cells survive radiation therapy and that pre-treatment with HDAC inhibitors may sensitise this resistant fraction.

Journal Article Type Article
Publication Date Dec 10, 2013
Journal British Journal of Cancer
Print ISSN 0007-0920
Electronic ISSN 1532-1827
Publisher Cancer Research UK
Peer Reviewed Peer Reviewed
Volume 109
Issue 12
Pages 3023-3033
Institution Citation Frame, F. M., Pellacani, D., Collins, A. T., Simms, M. S., Mann, V. M., Jones, G., …Maitland, N. J. (2013). HDAC inhibitor confers radiosensitivity to prostate stem-like cells. The British journal of cancer / Cancer Research Campaign, 109(12), 3023-3033. https://doi.org/10.1038/bjc.2013.691
DOI https://doi.org/10.1038/bjc.2013.691
Keywords Cancer Research; Oncology
Publisher URL https://www.nature.com/articles/bjc2013691
Additional Information From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

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Copyright Statement
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0




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