title: 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.
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.
authors: Department of Physiology, Justus Liebig University Giessen, Aulweg 129, D-35392 Giessen, Germany. heinrich.sauer@physiologie.med.uni-giessen.de
authors: Heinrich
authors: H
authors: Sauer
authors: Steffi
authors: S
authors: Engel
authors: Nada
authors: N
authors: Milosevic
authors: Fatemeh
authors: F
authors: Sharifpanah
authors: Maria
authors: M
authors: Wartenberg
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D020536:Enzyme Activators; D017382:Reactive Oxygen Species; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D000263:Adenylate Kinase; C505407:CASP3 protein, human; D053148:Caspase 3; C031143:AICA ribonucleotide