| AMPK and Akt determine apoptotic cell death following perturbations of one-carbon metabolism by regulating ER stress in acute lymphoblastic leukemia. | |
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MedLine Citation:
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PMID: 21262957 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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AICAr is a cell-permeable nucleotide that has been used in vivo and in vitro to activate AMPK. Our previous findings have shown that AICAr as a single agent induces dose- and time-dependent growth inhibition in acute lymphoblastic leukemia (ALL) cell lines. In addition, the combination of AICAr with antifolates [methotrexate (MTX) or pemetrexed] has been shown to further potentiate AMPK activation and to lead to greater cytotoxicity and growth inhibition in leukemia and other malignant cell types. Our data presented herein show that sustained endoplasmic reticulum (ER) stress is the predominant mechanism behind the synergistic induction of cell death by the combination of AICAr plus the inhibitor of one-carbon metabolism, MTX, in Bp- and T-ALL, as evidenced by induction of several unfolded protein response markers leading to apoptosis. We also show for the first time that AICAr in combination with MTX significantly induces Akt phosphorylation in ALL. Under these conditions, the concomitant inhibition of Akt, a cellular antagonist of AMPK, leads to further upregulation of AMPK activity and alleviates AICAr plus MTX-induced ER stress and apoptosis. Therefore, we also show that the concomitant activation of AMPK actually rescues the cells from AICAr plus MTX-induced ER stress and apoptosis. Our data suggest that the effects of AMPK activation on cell death or survival differ contextually depending on its signaling alterations with related oncogenic pathways and provide insight into the reported paradoxical proapoptotic versus prosurvival effects of AMPK activation. |
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Authors:
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Jeffim N Kuznetsov; Guy J Leclerc; Gilles M Leclerc; Julio C Barredo |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-01-24 |
Journal Detail:
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Title: Molecular cancer therapeutics Volume: 10 ISSN: 1538-8514 ISO Abbreviation: Mol. Cancer Ther. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-03-10 Completed Date: 2011-09-21 Revised Date: 2012-03-07 |
Medline Journal Info:
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Nlm Unique ID: 101132535 Medline TA: Mol Cancer Ther Country: United States |
Other Details:
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Languages: eng Pagination: 437-47 Citation Subset: IM |
Copyright Information:
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©2011 AACR. |
Affiliation:
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Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, 1580 NW 10 Ave, Miami, FL 33136, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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AMP-Activated Protein Kinases
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antagonists & inhibitors,
metabolism* Aminoimidazole Carboxamide / analogs & derivatives, pharmacology Apoptosis* / drug effects Carbon / metabolism Cell Line, Tumor / drug effects Cell Proliferation Drug Synergism Endoplasmic Reticulum / drug effects, genetics, metabolism* Humans Methotrexate / pharmacology Molecular Targeted Therapy Phosphorylation / drug effects Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*, pathology Proto-Oncogene Proteins c-akt / antagonists & inhibitors, metabolism* Ribonucleotides / pharmacology Signal Transduction / drug effects |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA098152-06/CA/NCI NIH HHS; R01-CA098152/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Ribonucleotides; 3031-94-5/AICA ribonucleotide; 360-97-4/Aminoimidazole Carboxamide; 59-05-2/Methotrexate; 7440-44-0/Carbon; EC 2.7.11.1/AMP-Activated Protein Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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