AMPK activation by AICAR sensitizes prostate cancer cells to radiotherapy

Rae, C. and Mairs, R. J. (2019) AMPK activation by AICAR sensitizes prostate cancer cells to radiotherapy. Oncotarget, 10(7), pp. 749-759. (doi: 10.18632/oncotarget.26598) (PMID:30774777) (PMCID:PMC6366825)

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Abstract

Although radiotherapy is often used to treat localized disease and for palliative care in prostate cancer patients, novel methods are required to improve the sensitivity of aggressive disease to ionizing radiation. AMP-activated protein kinase (AMPK) is an energy sensor which regulates proliferation, aggressiveness and survival of cancer cells. We assessed the ability of the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) to sensitize prostate cancer cells to radiation. Prostate cancer cell lines LNCaP and PC3 were treated with X-rays and AICAR then assessed for clonogenic survival, spheroid growth delay, cell cycle progression, and AMPK and p53 activity. AICAR synergistically enhanced the clonogenic killing capacity, spheroid growth inhibition and pro-apoptotic effect of X-rays. The mechanism of radiosensitization appeared to involve cell cycle regulation, but not oxidative stress. Moreover, it was not dependent on p53 status. Treatment of PC3 cells with a fatty acid synthase inhibitor further enhanced clonogenic killing of the combination of X-rays and AICAR, whereas mTOR inhibition caused no additional enhancement. These results indicate that interference with metabolic signalling pathways which protect cells against irradiation have the potential to enhance radiotherapy. Activation of AMPK in combination with radiotherapy has the potential to target metabolically active and aggressive tumors which are currently untreatable.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Rae, Dr Colin and Mairs, Professor Robert
Authors: Rae, C., and Mairs, R. J.
Subjects:R Medicine > RM Therapeutics. Pharmacology
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Oncotarget
Publisher:Impact Journals
ISSN:1949-2553
ISSN (Online):1949-2553
Copyright Holders:Copyright © 2019 Rae et al.
First Published:First published in Oncotarget 10(7): 749-759
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
743801Targeted radiotherapy of prostate cancer with drugs exploiting the aberrant metabolism of tumoursRobert MairsChief Scientist office (CSO)TCS/16/38ICS - EPIGENETICS