Activation of AMP-kinase by AICAR Induces Apoptosis of DU-145 Prostate Cancer Cells Through Generation of Reactive Oxygen Species and Activation of c-Jun N-terminal Kinase

Int J Oncol. 2012 Feb;40(2):501-8. doi: 10.3892/ijo.2011.1230. Epub 2011 Oct 13.

Abstract

The growth of cancer cells is limited by energy supply which is regulated by the energy sensor AMP-kinase (AMPK). Hence, mimicking a low energy state may inhibit cancer growth and may be exploited in anticancer therapies. In the present study, the impact of AMPK activation on cell growth and apoptosis of DU-145 prostate cancer cells was investigated. Incubation with the AMPK activator aminoimidazole carboxamide ribonucleotide (AICAR) dose-dependently inhibited cell growth, activated AMPK, and inhibited mTOR. Furthermore, AICAR treatment activated c-Jun N-terminal kinase (JNK) and caspase-3, thereby initiating apoptosis. Within 60 min of treatment AICAR raised intracellular reactive oxygen species (ROS) which could be abolished in the presence of the free radical scavenger N-(2-mercaptopropionyl)glycin (NMPG), the AMPK inhibitor compound C (Comp C) and the respiratory chain complex I inhibitor rotenone, but not by the NADPH oxidase inhibitor VAS2870. Inhibition of ROS generation abolished AMPK activation by AICAR as well as JNK and caspase-3 activation. Furthermore, AMPK activation, JNK phosphorylation and cleaved caspase-3 upon AICAR treatment were abolished in the presence of Comp C. In summary, our data demonstrate that activation of AMPK by AICAR induces apoptosis of prostate cancer cells by a signaling pathway involving ROS, activation of JNK and cleaved caspase-3.

MeSH terms

  • Adenylate Kinase / metabolism*
  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / pharmacology
  • Caspase 3 / metabolism
  • Cell Line, Tumor / drug effects
  • Cell Proliferation / drug effects
  • Enzyme Activation*
  • Enzyme Activators / pharmacology*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Male
  • Phosphorylation
  • Prostatic Neoplasms / enzymology*
  • Reactive Oxygen Species / metabolism*
  • Ribonucleotides / pharmacology*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Enzyme Activators
  • Reactive Oxygen Species
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Adenylate Kinase
  • CASP3 protein, human
  • Caspase 3
  • AICA ribonucleotide