AMPK activation by AICAR sensitizes prostate cancer cells to radiotherapy

Colin Rae,Robert J Mairs

doi:10.18632/oncotarget.26598

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.

Highlights

Prostate cancer is the most commonly diagnosed cancer amongst men and the second most common cause of cancer death in men [1]
Prostate cancer cell lines LNCaP and PC3 were treated with X-rays and AICAR assessed for clonogenic survival, spheroid growth delay, cell cycle progression, and AMPK and p53 activity
No further increase in cell kill resulted from treatment of PC3 cells with 3 mM AICAR, whereas LNCaP cells succumbed in a manner similar to that observed for PC3 cells

Summary

Introduction

Prostate cancer is the most commonly diagnosed cancer amongst men and the second most common cause of cancer death in men [1]. A hallmark of malignancy is abnormal metabolism which generates biomass and energy for proliferation, migration and cell signalling. Increased lipogenesis is observed in prostate cancer cells and is associated with their rapid growth and aggressiveness and inhibitors of fatty acid synthase (FASN) reduce cancer cell proliferation [5, 6]. Compared with their radiosensitive counterparts, radioresistant cancer cells have altered components of energy metabolism, including elevated levels and activity of FASN [7, 8]. In response to exposure to ionizing radiation, metabolic regulators such as 5’ adenosine monophosphate-activated protein kinase (AMPK) are activated [9]

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Conclusion