HDAC inhibitor confers radiosensitivity to prostate stem-like cells.
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, α2β1integrin(hi)/CD133(+)), transit-amplifying (TA, α2β1integrin(hi)/CD133(-)) and committed basal (CB, α2β1integrin(lo)) 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.


CONCLUSIONS
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.
YCR Cancer Research Unit, Department of Biology, University of York, Heslington, North Yorkshire, YO10 5DD, UK.
F M
FM
Frame
D
D
Pellacani
A T
AT
Collins
M S
MS
Simms
V M
VM
Mann
G D D
GD
Jones
M
M
Meuth
R G
RG
Bristow
N J
NJ
Maitland
D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation / Q000187:drug effects / Q000528:radiation effects; D020552:Comet Assay; D004249:DNA Damage; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology* / Q000528:radiation effects; D011470:Prostatic Hyperplasia / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011838:Radiation-Sensitizing Agents; C012589:trichostatin A