title: The Anticancer Agent, Di-2-Pyridylketone 4,4-Dimethyl-3-Thiosemicarbazone (Dp44mT), Up-Regulates the AMPK-Dependent Energy Homeostasis Pathway in Cancer Cells.
abstract: Adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy sensor that monitors ATP levels. There is also evidence that AMPK has onco-suppressive properties. Iron plays a crucial role in cellular energy transducing pathways and tumor cell proliferation. Therefore, metals (e.g., iron) could play an important role in the regulation of AMPK-dependent pathways. Hence, this investigation examined the effect of the iron and copper chelator and potent anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), on the AMPK-mediated pathway. These studies demonstrated that Dp44mT, which forms intracellular redox-active complexes with iron and copper, significantly activated AMPK (i.e., p-AMPK/AMPK ratio) in 5 different tumor cell-types. Furthermore, examination of the Dp44mT-metal complexes demonstrated that the effect of Dp44mT on AMPK was due to a dual mechanism: (1) its ability to chelate metal ions; and (2) the generation of reactive oxygen species (ROS). The activation of the AMPK-pathway by Dp44mT was mediated by the upstream kinase, liver kinase B1 (LKB1) that is a known tumor suppressor. Moreover, using AMPKα1-selective silencing, we demonstrated that Dp44mT activated AMPK, resulting in inhibition of acetyl CoA carboxylase 1 (ACC1) and raptor, and activation of Unc-51 like kinase (ULK1). These effects are vital for inhibition of fatty acid synthesis, suppression of protein synthesis and autophagic activation, respectively. Together, this AMPK-mediated repair response aims to rescue the loss of metal ions via chelation and the induction of cytotoxic damage mediated by redox cycling of the Dp44mT-metal ion complex. In conclusion, this study demonstrates for the first time that chelators target the AMPK-dependent pathway.
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia.
authors.forename: Sukriti
authors.initials: S
authors.lastname: Krishan
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia. Electronic address: d.richardson@usyd.med.edu.au.
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia. Electronic address: sumit.sahni@sydney.edu.au.
authors.forename: Sumit
authors.initials: S
authors.lastname: Sahni
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D000071189:Autophagy-Related Protein-1 Homolog / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005227:Fatty Acids / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D051379:Mice; D014176:Protein Biosynthesis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction; D013882:Thiosemicarbazones / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D005227:Fatty Acids; D047908:Intracellular Signaling Peptides and Proteins; D007502:Iron Chelating Agents; C463659:RPTOR protein, human; D017382:Reactive Oxygen Species; D000076223:Regulatory-Associated Protein of mTOR; D013882:Thiosemicarbazones; C539263:di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone; D007501:Iron; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C484754:ULK1 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C000588423:ACACA protein, human; D000103:Acetyl-CoA Carboxylase
keywords: AMPK; Anticancer Drug; Dp44mT; Energy Homeostasis; Molecular Pharmacology