HDAC inhibitor confers radiosensitivity to prostate stem-like cells

Area of Science:

• Oncology
• Cancer Biology
• Radiation Oncology

Background:

• Radiotherapy is a key treatment for prostate cancer, but tumor recurrence due to radiation resistance remains a challenge.
• Prostate cancer's cellular heterogeneity suggests a potential role for primitive stem-like cells in treatment resistance.

Purpose of the Study:

• To investigate the radioresistance of prostate cancer stem-like cells (SCs) compared to more differentiated cell populations.
• To explore the potential of histone deacetylase (HDAC) inhibitors as radiosensitizers for prostate cancer SCs.

Main Methods:

• Prostate epithelial cells were isolated and sorted into stem-like (SCs), transit-amplifying (TA), and committed basal (CB) populations.
• Radiosensitivity was assessed using colony-forming efficiency (CFE) and DNA damage assays (comet assay, DNA damage foci).
• Heterochromatin levels were measured, and the effect of the HDAC inhibitor Trichostatin A on radiosensitivity was evaluated.

Main Results:

• Prostate SCs exhibited significantly higher CFE post-irradiation compared to TA and CB cells.
• SCs sustained fewer lethal DNA double-strand breaks and possessed higher levels of heterochromatin, correlating with reduced proliferation.
• Treatment with an HDAC inhibitor sensitized SCs to radiation, reducing their survival.

Conclusions:

• Prostate cancer stem-like cells are inherently more radioresistant than differentiated prostate epithelial cells.
• These primitive SCs may represent the resistant cell fraction responsible for tumor recurrence after radiotherapy.
• Pre-treatment with HDAC inhibitors shows promise in sensitizing radioresistant prostate cancer SCs, potentially improving therapeutic efficacy.