Open AccessA novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis
Author(s) -
Zadra Giorgia,
Photopoulos Cornelia,
Tyekucheva Svitlana,
Heidari Pedram,
Weng Qing Ping,
Fedele Giuseppe,
Liu Hong,
Scaglia Natalia,
Priolo Carmen,
Sicinska Ewa,
Mahmood Umar,
Signoretti Sabina,
Birnberg Neal,
Loda Massimo
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201302734
Subject(s) - ampk , lipogenesis , androgen receptor , lncap , prostate cancer , cancer research , cell growth , activator (genetics) , chemistry , microbiology and biotechnology , biology , protein kinase a , kinase , endocrinology , medicine , receptor , lipid metabolism , biochemistry , 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 mTORC 1 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 mTORC 1 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.