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Title: Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A
Authors: Salas, Arelis
Ponnusamy, Suriyan
Senkal, Can E.
Meyers-Needham, Marisa
Selvam, Shanmugam Panneer
Saddoughi, Sahar A.
Apohan, Elif
Sentelle, R. David
Smith, Charles
Gault, Christopher R.
Obeid, Lina M.
El-Shewy, Hesham M.
Oaks, Joshua
Santhanam, Ramasamy
Marcucci, Guido
Baran, Yusuf
Mahajan, Sandeep
Fernandes, Daniel
Stuart, Robert
Perrotti, Danilo
Öğretmen, Besim
Keywords: Drug resistance
Chronic myeloid leukemia
Small interfering RNA
Cancer cells
Protein degradation
Publisher: American Society of Hematology
Source: Salas, A., Ponnusamy, S., Senkal, C. E., Meyers-Needham, M., Selvam, S. P., Saddoughi, S. A., Apohan, E., ... and Öğretmen, B. (2011). Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A. Blood, 117(22), 5941-5952. doi:10.1182/blood-2010-08-300772
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. © 2011 by The American Society of Hematology.
ISSN: 0006-4971
Appears in Collections:Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection
Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection

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