Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A

被引：103

作者：

Salas, Arelis ^{[1
,2
]}

Ponnusamy, Suriyan ^{[1
,2
]}

Senkal, Can E. ^{[1
,2
]}

Meyers-Needham, Marisa ^{[1
,2
]}

Selvam, Shanmugam Panneer ^{[1
,2
]}

Saddoughi, Sahar A. ^{[1
,2
]}

Apohan, Elif ^{[1
,2
]}

Sentelle, R. David ^{[1
,2
]}

Smith, Charles ^{[2
,3
]}

Gault, Christopher R. ^{[1
,2
]}

Obeid, Lina M. ^{[2
,4
]}

El-Shewy, Hesham M. ^{[5
]}

Oaks, Joshua ^{[6
]}

Santhanam, Ramasamy ^{[6
]}

Marcucci, Guido ^{[6
]}

Baran, Yusuf ^{[1
,2
]}

Mahajan, Sandeep ^{[1
,2
]}

Fernandes, Daniel ^{[1
,2
]}

Stuart, Robert ^{[2
]}

Perrotti, Danilo ^{[5
]}

Ogretmen, Besim ^{[1
,2
]}

机构：

[1] Ralph H Johnson Vet Adm Hosp, Dept Biochem & Mol Biol, Charleston, SC USA

[2] Ralph H Johnson Vet Adm Hosp, Hollings Canc Ctr, Charleston, SC USA

[3] Ralph H Johnson Vet Adm Hosp, Dept Pharmaceut Sci, Charleston, SC USA

[4] Ralph H Johnson Vet Adm Hosp, Div Internal Med, Charleston, SC USA

[5] Med Univ S Carolina, Div Endocrinol Diabet & Med Genet, Dept Med, Charleston, SC 29425 USA

[6] Ohio State Univ, Human Canc Genet Program, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA

来源：

BLOOD | 2011年 / 117卷 / 22期

基金：

美国国家卫生研究院;

关键词：

CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; IMATINIB-INDUCED APOPTOSIS; ABL TYROSINE KINASE; BCR-ABL; INHIBITOR STI571; GENE; SPHINGOSINE-1-PHOSPHATE; MECHANISMS; ANGIOGENESIS;

D O I：

10.1182/blood-2010-08-300772

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The mechanisms by which sphingosine kinase-1 (SK-1)/sphingosine 1-phosphate (S1P) activation contributes to imatinib resistance in chronic myeloid leukemia (CML) are unknown. We show herein that increased SK-1/S1P enhances Bcr-Abl1 protein stability, through inhibition of its proteasomal degradation in imatinibresistant K562/IMA-3 and LAMA-4/IMA human CML cells. In fact, Bcr-Abl1 stability was enhanced by ectopic SK-1 expression. Conversely, siRNA-mediated SK-1 knockdown in K562/IMA-3 cells, or its genetic loss in SK-1(-/-) MEFs, significantly reduced Bcr-Abl1 stability. Regulation of Bcr-Abl1 by SK-1/S1P was dependent on S1P receptor 2 (S1P2) signaling, which prevented Bcr-Abl1 dephosphorylation, and degradation via inhibition of PP2A. Molecular or pharmacologic interference with SK-1/S1P2 restored PP2A-dependent Bcr-Abl1 dephosphorylation, and enhanced imatinib-or nilotinib-induced growth inhibition in primary CD34(+) mononuclear cells obtained from chronic phase and blast crisis CML patients, K562/IMA-3 or LAMA4/IMA cells, and 32Dcl3 murine progenitor cells, ex-pressing the wild-type or mutant (Y253H or T315I) Bcr-Abl1 in situ. Accordingly, impaired SK-1/S1P2 signaling enhanced the growth-inhibitory effects of nilotinib against 32D/T315I-Bcr-Abl1-derived mouse allografts. Since SK-1/S1P/S1P2 signaling regulates Bcr-Abl1 stability via modulation of PP2A, inhibition of SK-1/S1P2 axis represents a novel approach to target wild-type-ormutant-Bcr-Abl1 thereby overcoming drug resistance. (Blood. 2011; 117(22): 5941-5952)

引用

页码：5941 / 5952

页数：12

共 50 条

[1] Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2 [J].

Alvarez, Sergio E. ;

Harikumar, Kuzhuvelil B. ;

Hait, Nitai C. ;

Allegood, Jeremy ;

Strub, Graham M. ;

Kim, Eugene Y. ;

Maceyka, Michael ;

Jiang, Hualiang ;

Luo, Cheng ;

Kordula, Tomasz ;

Milstien, Sheldon ;

Spiegel, Sarah .

NATURE, 2010, 465 (7301) :1084-U149

[2] Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL [J].

Azam, M ;

Latek, RR ;

Daley, GQ .

CELL, 2003, 112 (06) :831-843

[3] Alterations of ceramide/sphingosine 1-phosphate rheostat involved in the regulation of resistance to imatinib-induced apoptosis in K562 human chronic myeloid leukemia cells [J].

Baran, Yusuf ;

Salas, Arelis ;

Senkal, Can E. ;

Gunduz, Ufuk ;

Bielawski, Jacek ;

Obeid, Lina M. ;

Ogretmen, Besim .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (15) :10922-10934

[4] Deactivation of Sphingosine Kinase 1 by Protein Phosphatase 2A [J].

Barr, Renae K. ;

Lynn, Helen E. ;

Moretti, Paul A. B. ;

Khew-Goodall, Yeesim ;

Pitson, Stuart M. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (50) :34994-35002

[5] Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells [J].

Bonhoure, E. ;

Lauret, A. ;

Barnes, D. J. ;

Martin, C. ;

Malavaud, B. ;

Kohama, T. ;

Melo, J. V. ;

Cuvillier, O. .

LEUKEMIA, 2008, 22 (05) :971-979

[6] c-Ab1 has high intrinsic tyrosine kinase activity that is stimulated by mutation of the Src homology 3 domain and by autophosphorylation at two distinct regulatory tyrosines [J].

Brasher, BB ;

Van Etten, RA .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (45) :35631-35637

[7] Treating imatinib-resistant leukemia: The next generation targeted therapies [J].

Burgess, Michael R. ;

Sawyers, Charles L. .

THESCIENTIFICWORLDJOURNAL, 2006, 6 :918-930

[8] Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation [J].

Cattoretti, Giorgio ;

Mandelbaum, Jonathan ;

Lee, Nancy ;

Chaves, Alicia H. ;

Mahler, Ashley M. ;

Chadburn, Amy ;

Dalla-Favera, Riccardo ;

Pasqualucci, Laura ;

MacLennan, A. John .

CANCER RESEARCH, 2009, 69 (22) :8686-8692

[9] EXPRESSION OF A DISTINCTIVE BCR-ABL ONCOGENE IN PH1-POSITIVE ACUTE LYMPHOCYTIC-LEUKEMIA (ALL) [J].

CLARK, SS ;

MCLAUGHLIN, J ;

TIMMONS, M ;

PENDERGAST, AM ;

BEN-NERIAH, Y ;

DOW, LW ;

CRIST, W ;

ROVERA, G ;

SMITH, SD ;

WITTE, ON .

SCIENCE, 1988, 239 (4841) :775-777

[10] INDUCTION OF CHRONIC MYELOGENOUS LEUKEMIA IN MICE BY THE P210BCR/ABL GENE OF THE PHILADELPHIA-CHROMOSOME [J].

DALEY, GQ ;

VANETTEN, RA ;

BALTIMORE, D .

SCIENCE, 1990, 247 (4944) :824-830

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