Sphingosine kinase-1 mediates BCR/ABL-induced upregulation of Mcl-1 in chronic myeloid leukemia cells

Qf, Li; Wr, Huang; Hf, Duan; Wang, H; Wu, Chen-Tu; Ls, Wang

doi:10.1038/sj.onc.1210587

Cited by 65 publications

(51 citation statements)

References 21 publications

(20 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our previous data revealed an important role for SK1/ S1P signaling as a major mechanism of imatinib resistance by decreasing ceramide/S1P ratio in CML cells (Baran et al 2007). The role of SK1/S1P in drug resistance in CML was also conWrmed by independent studies (Bonhoure et al 2008;Li et al 2007). In the current study, we increased the intracellular concentrations of ceramide via inhibition of GCS and examined the possibility of enhancing apoptosis in response to imatinib in both sensitive and resistant cells.…”

Section: Discussionmentioning

confidence: 96%

Targeting glucosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation

Baran

Bielawski

Gündüz

et al. 2011

J Cancer Res Clin Oncol

View full text Add to dashboard Cite

Purpose Drug resistance presents a major obstacle for the treatment of some patients with chronic myeloid leukemia (CML). Pro-apoptotic ceramide mediates imatinib-induced apoptosis, and metabolism of ceramide by glucosylceramide synthase (GCS) activity, converting ceramide to glucosyl ceramide, might contribute to imatinib resistance. In this study, we investigated the role of ceramide metabolism by GCS in the regulation of imatinib-induced apoptosis in drug-sensitive and drug-resistant K562 and K562/IMA-0.2 and K562/IMA-1 human CML cells, which exhibit about 2.3-and 19-fold imatinib resistance, respectively. Methods Cytotoxic eVects of PDMP and imatinib were determined by XTT cell proliferation assay. Expression levels of GCS were determined by RT-PCR and western blot. Intracellular ceramide levels were determined by LC-MS. Cell viability analyses was conducted by Trypan blue dye exclusion assay. Cell cycle and apoptosis analyses were examined by Xow cytometry. Results We Wrst showed that mRNA and protein levels of GCS are increased in drug-resistant K562/IMA as compared to sensitive K562 cells. Next, forced expression of GCS in sensitive K562 cells conferred resistance to imatinib-induced apoptosis. In reciprocal experiments, targeting GCS using its known inhibitor, PDMP, enhanced ceramide accumulation and increased cell death in response to imatinib in K562/IMA cells. Conclusion Our data suggest the involvement of GCS in resistance to imatinib-induced apoptosis, and that targeting GCS by PDMP increased imatinib-induced cell death in drug-sensitive and drug-resistant K562 cells via enhancing ceramide accumulation.

show abstract

Section: Discussionmentioning

confidence: 96%

Targeting glucosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation

Baran

Bielawski

Gündüz

et al. 2011

J Cancer Res Clin Oncol

View full text Add to dashboard Cite

show abstract

“…on June 7, 2019. by guest www.bloodjournal.org From MCL1 and reduced cell survival. 19,61 Interestingly, however, MP-A08 treatment was also associated with induction of the proapoptotic BH3-only proteins BIM, NOXA, and cleaved BID, which was not observed previously when AML cell lines were exposed to another SPHK1 inhibitor, SKI-178. 19 Notably, our findings demonstrate a role of S1PR2 in maintaining MCL1 expression because application of the S1PR2 antagonist JTE-013, but not antagonists of S1PR1, 3, and 4, induced a similar loss of MCL1 in AML cells to that observed with SPHK1 inhibitors.…”

Section: Org Frommentioning

confidence: 87%

Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia

Powell

Lewis

Zhu

et al. 2017

Blood

View full text Add to dashboard Cite

Key Points• Inhibition of SPHK1 in human AML cells induces MCL1 degradation and caspasedependent cell death.• SPHK1 inhibitors reduce leukemic burden and prolong survival in orthotopic patientderived xenografts of AML.Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy and bone marrow transplantation, overall survival remains poor. Sphingosine kinase 1 (SPHK1) generates the bioactive lipid sphingosine 1-phosphate (S1P) and has established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers. The role and targeting of SPHK1 in primary AML, however, has not been previously investigated. Here we show that SPHK1 is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SPHK1 induced caspase-dependent cell death in AML cell lines, primary AML patient blasts, and isolated AML patient leukemic progenitor/stem cells, with negligible effects on normal bone marrow CD34 1 progenitors from healthy donors. Furthermore, administration of SPHK1 inhibitors to orthotopic AML patient-derived xenografts reduced tumor burden and prolonged overall survival without affecting murine hematopoiesis. SPHK1 inhibition was associated with reduced survival signaling from S1P receptor 2, resulting in selective downregulation of the prosurvival protein MCL1. Subsequent analysis showed that the combination of BH3 mimetics with either SPHK1 inhibition or S1P receptor 2 antagonism triggered synergistic AML cell death. These results support the notion that SPHK1 is a bona fide therapeutic target for the treatment of AML. (Blood. 2017;129(6):771-782)

show abstract

“…18,40,41 However, mechanisms of this process, especially the involvement of S1P2 signaling via activation of PP2A in the regulation of Bcr-Abl1 (wt and mutants) and drug resistance were unknown, which is revealed for the first time in this study. Previously, increased ceramide generation was implicated in imatinib-induced apoptosis in K562 cells, and alterations of ceramide/S1P rheostat was reported to mediate TKI resistance.…”

Section: Discussionmentioning

confidence: 97%

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

Salas

Ponnusamy

Senkal

et al. 2011

Blood

104

106

View full text Add to dashboard Cite

Introduction CML is a clonal disorder of pluripotent hematopoietic stem cells characterized by the Philadelphia (Ph) chromosome, which results from the reciprocal translocation between the long arms of chromosomes 9 and 22. 1-4 This hybrid B-cell receptor (BCR)-ABL1 gene encodes for a fusion protein Bcr-Abl1 with a constitutive tyrosine kinase activity. 3,4 Despite high rates of clinical responses in early chronic phase CML (CML-CP) to the Bcr-Abl1 kinase inhibitor imatinib, 5-8 development of resistance is a major problem in late CML-CP and in the treatment of blast crisis CML (CML-BC). 9-12 Although Bcr-Abl1-independent mechanisms also exist, 13-15 resistance in CML-CP is usually associated with the expression of mutant Bcr-Abl1 proteins, including T315I and Y253F/H mutations against which the second generation ABL tyrosine kinase inhibitors (TKI) such as nilotinib and/or dasatinib show limited effect. 15-17 Nonetheless , BCR-ABL1 mutations may not account for all cases of drug resistance in CML (CP and BC); indeed, alternative Bcr-Abl1-dependent mechanisms including alterations of sphingolipid metabolism and signaling, 18 might account for TKI resistance. Sphingolipids, ceramide and sphingosine 1-phosphate (S1P) included, are a family of membrane lipids with important roles in the regulation of the fluidity and subdomain structure of membranes. 19-21 Ceramide can be hydrolyzed by ceramidases to release sphingosine, which is phosphorylated by sphingosine kinases-1 or-2 (SK-1 or SK-2) to generate S1P. 20 Ceramide plays proapoptotic roles 21 whereas S1P mediates proliferation and/or resistance to apoptosis 22,23 generally via G-protein-coupled S1P1-5 receptor signaling. 24 However, receptor-independent intracellular functions of S1P were also reported. 25 Recently, alteration of the balance between the proapoptotic ceramide and antiapoptotic S1P via up-regulation of SK-1 was shown to mediate imatinib resistance in K562 CML-BC patient-derived cells by an unknown mechanism. 18 Here, we report the identification of a novel mechanism by which SK-1/S1P mediates imatinib resistance by regulation of the PP2A-dependent and SHP-1-mediated Bcr-Abl1 dephosphoryla-tion and stability selectively via receptor 2 (S1P2) signaling in CML (CP and BC). In addition, our data suggest that targeting the SK-1/S1P2 signaling axis provides a novel strategy to modulate wild-type (wt) or mutant (T315I or Y253H) Bcr-Abl1 stability by restoring PP2A function, and attenuate drug resistance both in cell culture and in mice bearing 32D/T315I-Bcr-Abl1 allografts. Human CML cell lines K562, LAMA4, and their imatinib-resistant derivatives K562/IMA-0.1,-1,-3, or LAMA4/IMA, were maintained as described. 18 The Bcr-Abl-expressing 32Dcl3 cells, 32D-p210 Bcr-Abl (wt), 32D-p210 Bcr-Abl (Y253H) and (T315I) were maintained in RPMI containing 15% FBS, 2mM L-glutamine, and penicillin and streptomycin (P/S; 100 ng/mL each). MEFs (wt and SK-1 /) were maintained in DMEM with 10% FBS and P/S. Human CD34 primary cells from CML patients and normal donor were obt...

show abstract

Sphingosine kinase-1 mediates BCR/ABL-induced upregulation of Mcl-1 in chronic myeloid leukemia cells

Cited by 65 publications

References 21 publications

Targeting glucosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation

Targeting glucosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation

Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia

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

Contact Info

Product

Resources

About