title: Regulation of the kinase RSK1 by arsenic trioxide and generation of antileukemic responses.
abstract: Arsenic Trioxide (As₂O₃) is one of the most effective agents in the treatment of acute promyelocytic leukemia (APL), but has no significant efficacy in other forms of AML. The mechanisms of relative resistance of non-APL cells are not well understood, but emerging evidence suggests that activation of negative feedback regulatory loops and pathways contributes to such resistance. We provide evidence that a signaling cascade involving the kinase RSK1 is engaged in a negative feedback manner during arsenic-treatment of cells and exhibits regulatory effects on growth and survival of AML cells in response to treatment with As₂O₃. Our data demonstrate that pharmacological inhibition or molecular disruption of expression of RSK1 enhances As₂O₃-dependent apoptosis and/or growth inhibition of AML cells. Importantly, combination of a pharmacological inhibitor of RSK and As₂O₃ results in enhanced suppression of primary AML leukemic progenitors. Altogether, our findings suggest an important regulatory role for RSK1 in the generation of the effects of As₂O₃ in AML cells. They also raise the potential of RSK1 targeting in combination with As₂O₃ as a novel approach to promote antileukemic responses.
authors: Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
authors: John P
authors: JP
authors: Galvin
authors: Jessica K
authors: JK
authors: Altman
authors: Amy
authors: A
authors: Szilard
authors: Dennis J
authors: DJ
authors: Goussetis
authors: Eliza
authors: E
authors: Vakana
authors: Antonella
authors: A
authors: Sassano
authors: Leonidas C
authors: LC
authors: Platanias
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D001152:Arsenicals; D010087:Oxides; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D000077237:Arsenic Trioxide
keywords: RSK1; acute myeloid leukemia; arsenic trioxide; kinase
references: Leukemia. 2008 Apr;22(4):686-707
references: 18337767
references: Blood. 1999 Nov 15;94(10):3315-24
references: 10552940
references: Immunol Res. 2011 Apr;49(1-3):248-68
references: 21170740
references: Biochem J. 2012 Jan 15;441(2):553-69
references: 22187936
references: Cancer Res. 2007 May 1;67(9):4524-32
references: 17483369
references: J Clin Oncol. 2001 Sep 15;19(18):3852-60
references: 11559723
references: J Biol Chem. 2008 Jan 25;283(4):1992-2001
references: 18048359
references: Blood. 2012 Oct 25;120(17):3555-62
references: 22898604
references: Blood. 1994 Mar 15;83(6):1603-11
references: 8123851
references: Leukemia. 2008 Apr;22(4):708-22
references: 18337766
references: Nat Rev Mol Cell Biol. 2008 Oct;9(10):747-58
references: 18813292
references: Blood. 2011 Jun 23;117(25):6885-94
references: 21527514
references: J Biol Chem. 2003 Dec 5;278(49):49254-60
references: 14504289
references: Blood. 2010 Sep 30;116(13):2324-31
references: 20574048
references: Curr Pharm Des. 2005;11(21):2779-95
references: 16101455
references: J Biol Chem. 2006 Aug 11;281(32):22446-52
references: 16762916
references: Mol Cancer Ther. 2009 Mar;8(3):615-25
references: 19240159
references: Clin Cancer Res. 2011 Jul 1;17(13):4378-88
references: 21415215
references: Blood. 2010 Mar 18;115(11):2127-35
references: 20075156
references: Proc Natl Acad Sci U S A. 2008 May 6;105(18):6584-9
references: 18451027
references: Blood. 2008 Sep 15;112(6):2450-62
references: 18583568
references: Leuk Res. 2004 Sep;28(9):909-19
references: 15234567
references: Mol Pharmacol. 2010 May;77(5):828-35
references: 20159944
references: J Biol Chem. 2001 Jul 27;276(30):28570-7
references: 11353767
references: Blood. 1997 May 1;89(9):3354-60
references: 9129042
references: J Biol Chem. 2010 Sep 24;285(39):29989-97
references: 20656687
references: Mol Cancer Ther. 2006 Nov;5(11):2815-23
references: 17121928
references: Biochim Biophys Acta. 2007 Aug;1773(8):1263-84
references: 17126425
references: Leukemia. 2003 Sep;17(9):1783-93
references: 12970778
references: J Biol Chem. 1995 Jul 7;270(27):15938-41
references: 7608146
references: Oncogene. 2013 Aug 22;32(34):3923-32
references: 23246968
references: Blood. 1999 May 1;93(9):3074-80
references: 10216104
references: Curr Biol. 2008 Sep 9;18(17):1269-77
references: 18722121
references: Blood. 2011 Dec 8;118(24):6399-402
references: 22021366
references: J Biol Chem. 2002 Nov 22;277(47):44988-95
references: 12239215
references: Mol Cell. 2010 Feb 12;37(3):299-310
references: 20159550
references: Blood. 2010 Nov 11;116(19):3751-7
references: 20705755
references: J Biol Chem. 2008 May 2;283(18):12034-42
references: 18299328
references: Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12469-74
references: 20616057
references: Front Biosci. 2008 May 01;13:4258-75
references: 18508509
references: Leuk Lymphoma. 2011 Feb;52 Suppl 1:45-53
references: 21299459
references: Cancer Res. 2005 Aug 15;65(16):7338-47
references: 16103085
references: J Biol Chem. 2002 Mar 8;277(10):7726-35
references: 11773065
references: Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13489-94
references: 15342917
references: Leukemia. 2011 Jul;25(7):1080-94
references: 21494257
references: J Biol Chem. 2009 Jul 10;284(28):18583-7
references: 19363033
references: Cancer Res. 2006 Jul 1;66(13):6763-71
references: 16818652