Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A
Küçük Resim Yok
Tarih
2011
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
American Society of Hematology
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
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.
Açıklama
Anahtar Kelimeler
4 (2,6 dichloro 4 pyridinyl) 1 (1,3 dimethyl 4 isopropyl 1h pyrazolo[3,4 b]pyridin 6 yl)semicarbazide, BCR ABL protein, BCR ABL1 protein, imatinib, lactacystin, nilotinib, phosphoprotein phosphatase 2A, small interfering RNA, sphingosine 1 phosphate receptor, sphingosine 1 phosphate receptor 2, sphingosine kinase 1, unclassified drug, animal experiment, article, cancer cell culture, cancer resistance, cell growth, chronic myeloid leukemia, controlled study, drug mechanism, drug targeting, enzyme activation, human, human cell, mouse, nonhuman, priority journal, protein degradation, protein dephosphorylation, protein expression, protein stability, signal transduction, therapy resistance
Kaynak
Blood
WoS Q Değeri
Scopus Q Değeri
Q1
Cilt
117
Sayı
22
