Resveratrol enhances prostate cancer cell response to ionizing radiation. Modulation of the AMPK, Akt and mTOR pathways.
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, p21(cip1) and p27(kip1). 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-p21(cip1)/p27(kip1) and inhibit the Akt signalling pathways.
Translational Radiation Biology Laboratory, Juravinski Cancer Centre, Hamilton, Ontario, Canada.
Ayesha
A
Rashid
Caiqiong
C
Liu
Toran
T
Sanli
Evangelia
E
Tsiani
Gurmit
G
Singh
Robert G
RG
Bristow
Ian
I
Dayes
Himu
H
Lukka
James
J
Wright
Theodoros
T
Tsakiridis
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D016193:G1 Phase; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence / Q000379:methods; D011471:Prostatic Neoplasms / Q000532:radiotherapy*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011839:Radiation, Ionizing; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol