A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • February 4, 2014

Research

keywords

  • AMP-Activated Protein Kinases
  • Cell Proliferation
  • Enzyme Activators
  • Lipogenesis
  • Prostatic Neoplasms

Identity

PubMed Central ID

  • PMC3992078

Scopus Document Identifier

  • 84898601973

Digital Object Identifier (DOI)

  • 10.1002/emmm.201302734

PubMed ID

  • 24497570

Additional Document Info

volume

  • 6

issue

  • 4