See also: MJ Schiewer & KE Knudsen (April 2014)
A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis
Version of Record online: 4 FEB 2014
© 2014 The Authors.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 6, Issue 4, pages 519–538, April 2014
How to Cite
EMBO Mol Med (2014) 6, 519–538
- Issue online: 2 APR 2014
- Version of Record online: 4 FEB 2014
- Manuscript Accepted: 16 DEC 2013
- Manuscript Revised: 14 DEC 2013
- Manuscript Received: 9 MAR 2013
- Prostate Cancer Foundation
- DF/HCC SPORE in Prostate Cancer. Grant Number: NIH/NCI P50 CA90381
- NIH. Grant Number: RO1CA131945
- American Italian Cancer Foundation
- Andrea e Libi Lorini Foundation
Vol. 6, Issue 10, 1357, Version of Record online: 1 SEP 2014
- AMPK direct activation;
- androgen signaling inhibitors;
- de novo lipogenesis;
- MT 63–78;
- prostate cancer
5′AMP-activated kinase (AMPK) constitutes a hub for cellular metabolic and growth control, thus representing an ideal therapeutic target for prostate cancers (PCas) characterized by increased lipogenesis and activation of mTORC1 pathway. However, whether AMPK activation itself is sufficient to block cancer cell growth remains to be determined. A small molecule screening was performed and identified MT 63–78, a specific and potent direct AMPK activator. Here, we show that direct activation of AMPK inhibits PCa cell growth in androgen sensitive and castration resistant PCa (CRPC) models, induces mitotic arrest, and apoptosis. In vivo, AMPK activation is sufficient to reduce PCa growth, whereas the allelic loss of its catalytic subunits fosters PCa development. Importantly, despite mTORC1 blockade, the suppression of de novo lipogenesis is the underpinning mechanism responsible for AMPK-mediated PCa growth inhibition, suggesting AMPK as a therapeutic target especially for lipogenesis-driven PCas. Finally, we demonstrate that MT 63–78 enhances the growth inhibitory effect of AR signaling inhibitors MDV3100 and abiraterone. This study thus provides a rationale for their combined use in CRPC treatment.
Direct activation of AMPK with a novel, highly specific compound curbs prostate cancer growth via inhibition of de novo lipogenesis. The combination of AMPK activation and hormonal therapy results in a synergistic anti-cancer effect.
- Direct activation of AMPK inhibits prostate cancer growth in vitro and in vivo.
- Androgen receptor signaling inhibitors and AMPK activators act synergistically.
- Persistent activation of AMPK results in mitotic arrest and apoptosis of prostate cancer cells.
- Inhibition of de novo lipogenesis is the key mechanism of AMPK-mediated anti-tumor effect.
- MT 63–78 is a novel, highly specific direct activator of AMPK.