A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis.
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.
Department of Medical Oncology, Dana-Farber Cancer Institute Harvard Medical School, Boston, MA, USA.
Giorgia
G
Zadra
Cornelia
C
Photopoulos
Svitlana
S
Tyekucheva
Pedram
P
Heidari
Qing Ping
QP
Weng
Giuseppe
G
Fedele
Hong
H
Liu
Natalia
N
Scaglia
Carmen
C
Priolo
Ewa
E
Sicinska
Umar
U
Mahmood
Sabina
S
Signoretti
Neal
N
Birnberg
Massimo
M
Loda
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D020536:Enzyme Activators / Q000008:administration & dosage*; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology*
D020536:Enzyme Activators; D055372:AMP-Activated Protein Kinases