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Resveratrol enhances prostate cancer cell response to ionizing radiation. Modulation of the AMPK, Akt and mTOR pathways

Ayesha Rashid12, Caiqiong Liu1, Toran Sanli13, Evangelia Tsiani4, Gurmit Singh3, Robert G Bristow5, Ian Dayes2, Himu Lukka2, James Wright2 and Theodoros Tsakiridis12*

Author Affiliations

1 Translational Radiation Biology Laboratory, Juravinski Cancer Centre, 699 Concession Street, Hamilton, Ontario, L84 5C2, Canada

2 Department of Oncology, McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4L8, Canada

3 Department of Pathology and Molecular Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4L8, Canada

4 Department of Community Health Science, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario, L2S 3A1, Canada

5 Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada

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Radiation Oncology 2011, 6:144  doi:10.1186/1748-717X-6-144

Published: 26 October 2011

Abstract

Background

Prostate cancer (PrCa) displays resistance to radiotherapy (RT) and requires radiotherapy dose escalation which is associated with greater toxicity. This highlights a need to develop radiation sensitizers to improve the efficacy of RT in PrCa. Ionizing radiation (IR) stimulates pathways of IR-resistance and survival mediated by the protein kinase Akt but it also activates the metabolic energy sensor and tumor suppressor AMP-Activated Protein Kinase (AMPK). Here, we examined the effects of the polyphenol resveratrol (RSV) on the IR-induced inhibition of cell survival, modulation of cell cycle and molecular responses in PrCa cells.

Methods

Androgen-insensitive (PC3), sensitive (22RV1) PrCa and PNT1A normal prostate epithelial cells were treated with RSV alone (2.5-10 μM) or in combination with IR (2-8 Gy). Clonogenic assays, cell cycle analysis, microscopy and immunoblotting were performed to assess survival, cell cycle progression and molecular responses.

Results

RSV (2.5-5 μM) inhibited clonogenic survival of PC3 and 22RV1 cells but not of normal prostate PNT1A cells. RSV specifically sensitized PrCa cells to IR, induced cell cycle arrest at G1-S phase and enhanced IR-induced nuclear aberrations and apoptosis. RSV enhanced IR-induced expression of DNA damage (γH2Ax) and apoptosis (cleaved-caspase 3) markers as well as of the cell cycle regulators p53, p21cip1 and p27kip1. RSV enhanced IR-activation of ATM and AMPK but inhibited basal and IR-induced phosphorylation of Akt.

Conclusions

Our results suggest that RSV arrests cell cycle, promotes apoptosis and sensitizes PrCa cells to IR likely through a desirable dual action to activate the ATM-AMPK-p53-p21cip1/p27kip1 and inhibit the Akt signalling pathways.

Keywords:
radio-sensitizers; clonogenic survival; cell cycle; ATM; p53; p21cip1