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

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dc.authorscopusid7102443095
dc.authorscopusid59100721500
dc.authorscopusid6504075529
dc.authorscopusid37038064700
dc.authorscopusid37038449200
dc.authorscopusid6602946279
dc.authorscopusid8360674500
dc.contributor.authorSalas A.
dc.contributor.authorPonnusamy S.
dc.contributor.authorSenkal C.E.
dc.contributor.authorMeyers-Needham M.
dc.contributor.authorSelvam S.P.
dc.contributor.authorSaddoughi S.A.
dc.contributor.authorApohan E.
dc.date.accessioned2024-08-04T19:59:05Z
dc.date.available2024-08-04T19:59:05Z
dc.date.issued2011
dc.departmentİnönü Üniversitesien_US
dc.description.abstractThe 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.en_US
dc.description.sponsorshipNational Institute of Dental and Craniofacial Research, NIDCR: R01DE016572; National Institute of Dental and Craniofacial Research, NIDCRen_US
dc.identifier.doi10.1182/blood-2010-08-300772
dc.identifier.endpage5952en_US
dc.identifier.issn0006-4971
dc.identifier.issue22en_US
dc.identifier.pmid21527515en_US
dc.identifier.scopus2-s2.0-79957980683en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage5941en_US
dc.identifier.urihttps://doi.org/10.1182/blood-2010-08-300772
dc.identifier.urihttps://hdl.handle.net/11616/90358
dc.identifier.volume117en_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherAmerican Society of Hematologyen_US
dc.relation.ispartofBlooden_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject4 (2,6 dichloro 4 pyridinyl) 1 (1,3 dimethyl 4 isopropyl 1h pyrazolo[3,4 b]pyridin 6 yl)semicarbazideen_US
dc.subjectBCR ABL proteinen_US
dc.subjectBCR ABL1 proteinen_US
dc.subjectimatiniben_US
dc.subjectlactacystinen_US
dc.subjectnilotiniben_US
dc.subjectphosphoprotein phosphatase 2Aen_US
dc.subjectsmall interfering RNAen_US
dc.subjectsphingosine 1 phosphate receptoren_US
dc.subjectsphingosine 1 phosphate receptor 2en_US
dc.subjectsphingosine kinase 1en_US
dc.subjectunclassified drugen_US
dc.subjectanimal experimenten_US
dc.subjectarticleen_US
dc.subjectcancer cell cultureen_US
dc.subjectcancer resistanceen_US
dc.subjectcell growthen_US
dc.subjectchronic myeloid leukemiaen_US
dc.subjectcontrolled studyen_US
dc.subjectdrug mechanismen_US
dc.subjectdrug targetingen_US
dc.subjectenzyme activationen_US
dc.subjecthumanen_US
dc.subjecthuman cellen_US
dc.subjectmouseen_US
dc.subjectnonhumanen_US
dc.subjectpriority journalen_US
dc.subjectprotein degradationen_US
dc.subjectprotein dephosphorylationen_US
dc.subjectprotein expressionen_US
dc.subjectprotein stabilityen_US
dc.subjectsignal transductionen_US
dc.subjecttherapy resistanceen_US
dc.titleSphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2Aen_US
dc.typeArticleen_US

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