Activation of AMPK sensitizes prostate cancer cells to experimental radiotherapy


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Colin Rae1,Robert Mairs1
1University of Glasgow

Abstract

Background

Although radiotherapy is widely used in the treatment of prostate cancer, damage to neighbouring normal organs limits the radiation dose which can be delivered.  Activation of the energy-sensing AMP-activated protein kinase (AMPK) pathway decreases proliferation, increases apoptosis of cancer cells and inhibits tumour growth in pre-clinical models.  We aim to combine drugs affecting the AMPK signalling pathways involved in radiation response and metabolic activity of cancer cells with experimental radiotherapy in order to enhance its cancer killing activity.

Method

The efficacy of drugs alone and in combination with x-radiation was assessed using PC3 and LNCaP prostate carcinoma cells cultured as monolayers or multicellular tumour spheroids.  Cell cycle regulation and apoptosis was evaluated in propidium iodide stained cells.

Results

AICAR (AMPK activator) decreased clonogenic survival and spheroid growth rate when administered as a single agent.  Furthermore, the radiosensitising effect of AICAR was indicated by enhancement of the radiation-induced clonogenic kill, spheroid growth delay and apoptotic cell death.  Combination index analysis also indicated synergistic interaction between ionising radiation and AICAR.  Cell cycle arrest induced by x-irradiation was prevented by AICAR in both cell lines, suggesting a method of interaction resulting in radiosensitization, regardless of the p53 status of the cells.

Conclusion

Interference with intracellular signalling pathways which protect cancer cells against ionising radiation have the potential to enhance the effect of radiotherapy.  We have demonstrated that activation of the AMPK pathway sensitized cancer cells to radiation and suggest that this novel method of enhancing radiotherapy of prostate cancer will target the most metabolically active cells with the highest potential for proliferation and metastatic spread.