Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Arelis Salas1,2,*,
  2. Suriyan Ponnusamy1,2,*,
  3. Can E. Senkal1,2,
  4. Marisa Meyers-Needham1,2,
  5. Shanmugam Panneer Selvam1,2,
  6. Sahar A. Saddoughi1,2,
  7. Elif Apohan1,2,
  8. R. David Sentelle1,2,
  9. Charles Smith2,3,
  10. Christopher R. Gault1,2,
  11. Lina M. Obeid2,4,
  12. Hesham M. El-Shewy5,
  13. Joshua Oaks6,
  14. Ramasamy Santhanam6,
  15. Guido Marcucci6,
  16. Yusuf Baran1,2,
  17. Sandeep Mahajan1,2,
  18. Daniel Fernandes1,2,
  19. Robert Stuart2,
  20. Danilo Perrotti5, and
  21. Besim Ogretmen1,2
  1. 1Department of Biochemistry and Molecular Biology,
  2. 2Hollings Cancer Center,
  3. 3Department of Pharmaceutical Sciences,
  4. 4Division of Internal Medicine, Ralph H. Johnson Veterans Administration Hospital, and
  5. 5Division of Endocrinology, Diabetes, and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC; and
  6. 6Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH

Abstract

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 imatinib-resistant 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, expressing 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- or mutant-Bcr–Abl1 thereby overcoming drug resistance.

  • Submitted August 5, 2010.
  • Accepted April 14, 2011.
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