Suppression of cancer stem-like cell radioresistance by inhibiting AMPK signaling

Cancer stem cell (CSC) radioresistance is a major cause of radiotherapy (RT) failure and tumor recurrence. The molecular target for eradicating CSCs has not been identified despite research efforts to overcome tumor radioresistance. The adenosine monophosphate-activated protein kinase (AMPK) is responsible for transmitting nuclear DNA damage signals to the mitochondria, which in turn generate adenosine triphosphate to execute a DNA damage response. Disruption of this mitochondria-mediated genomic defense mechanism may be an effective strategy to enhance the cytotoxic efficacy of RT. Here, we investigated the potential efficacy of the pan-AMPK inhibitor dorsomorphin (Dor) in preventing CSC radioresistance. Radioresistant cancer stem-like cells were derived from the human liver cancer cell line HepG2 (HepG2 82FR-31NR). The radiosensitizing effect of Dor was then examined in HepG2 82FR-31NR cell cultures by clonogenic assays. Low-dose Dor markedly suppressed the recovery of HepG2 cancer stem-like cells after radiation but had little effect on normal fibroblast proliferation and survival, whether applied alone or in combination with radiation. In conclusion, this study strongly suggests that Dor treatment can radiosensitize cancer stem-like cells at doses that have no significant cytotoxic effects on normal human fibroblasts.