AMPK and Akt determine apoptotic cell death following perturbations of one-carbon metabolism by regulating ER stress in acute lymphoblastic leukemia.
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.
Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, 1580 NW 10 Ave, Miami, FL 33136, USA.
Jeffim N
JN
Kuznetsov
Guy J
GJ
Leclerc
Gilles M
GM
Leclerc
Julio C
JC
Barredo
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002244:Carbon / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D010766:Phosphorylation / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D002244:Carbon; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D008727:Methotrexate
Mol Cancer Ther. 2006 Sep;5(9):2211-7
16985054
Inflamm Res. 2005 Jul;54(7):273-80
16134056
Cancer Res. 2005 Mar 15;65(6):2441-8
15781660
N Engl J Med. 1998 Aug 27;339(9):605-15
9718381
J Physiol. 2006 Jul 1;574(Pt 1):63-71
16613876
Biochim Biophys Acta. 2010 Apr;1804(4):918-28
20097313
J Biol Chem. 2006 Mar 3;281(9):5335-40
16340011
Eur J Biochem. 1997 Jun 1;246(2):259-73
9208914
J Mol Signal. 2010 Sep 23;5:15
20863384
Nat Med. 2007 Oct;13(10):1203-10
17873882
Mol Cell Biol. 2005 Nov;25(21):9554-75
16227605
Mol Cancer Ther. 2009 Apr;8(4):733-41
19372545
Apoptosis. 2009 Feb;14(2):218-25
19130236
Mol Cancer. 2007 Jul 10;6:46
17623090
Cardiovasc Res. 1993 Jan;27(1):43-7
8458030
J Biol Chem. 2001 Dec 14;276(50):46912-6
11598104
Thromb Haemost. 2010 May;103(5):1022-32
20216988
Nature. 1998 Jan 8;391(6663):184-7
9428765
J Biol Chem. 2005 Sep 16;280(37):32081-9
16027121
J Clin Invest. 1993 Dec;92(6):2675-82
8254024
N Engl J Med. 2006 Jan 12;354(2):166-78
16407512
Biol Pharm Bull. 2010;33(10):1644-9
20930370
J Biol Chem. 1998 Dec 11;273(50):33533-9
9837934
Mol Pharmacol. 1997 Jul;52(1):155-63
9224825
J Biol. 2003;2(4):28
14511394
EMBO J. 2009 Mar 18;28(6):677-85
19197243
Trends Biochem Sci. 1999 Jan;24(1):22-5
10087918
Oncology. 2004;67(5-6):476-9
15714005
Environ Toxicol Pharmacol. 2011 Jan;31(1):18-24
21787665
Diabetes. 2006 Apr;55(4):865-74
16567505
Mol Cancer Ther. 2005 Oct;4(10):1533-40
16227402
Cancer Res. 2009 Jul 1;69(13):5467-74
19549896
Cell Signal. 2003 Jun;15(6):585-95
12681446
BMJ. 2002 Feb 2;324(7332):283-7
11823363
Biomaterials. 2006 Mar;27(9):1803-9
16289659
Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E635-46
19158325
Protein Sci. 2004 Jan;13(1):155-65
14691231
Blood. 1994 Jul 15;84(2):564-9
7517720