Inhibition of Protein Phosphatase 2A (PP2A) Prevents Mcl-1 Protein Dephosphorylation at the Thr-163/Ser-159 Phosphodegron, Dramatically Reducing Expression in Mcl-1-amplified Lymphoma Cells

Nifoussi, Shanna K.; Ratcliffe, Nora R.; Ornstein, Deborah L.; Kasof, Gary M.; Strack, Stefan; Craig, Ruth W.

doi:10.1074/jbc.m114.587873

Cited by 16 publications

(17 citation statements)

References 70 publications

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“…64 Because stability of MCL1 is also regulated by phosphorylation, 65 it is tempting to speculate that such a mechanism may also operate to regulate MCL1 expression. Notably, however, inhibition of PP2A has been recently shown to enhance MCL1 degradation in lymphoma cells, 66 suggesting the situation may be more complex.…”

Section: Org Frommentioning

confidence: 99%

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

Powell

Lewis

Zhu

et al. 2017

Blood

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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)

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Section: Org Frommentioning

confidence: 99%

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

Powell

Lewis

Zhu

et al. 2017

Blood

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“…The stability of MCL1 is mainly controlled by its phosphorylation status. 38,39 Phosphorylated MCL1 can be an easy target of an E3 ubiquitin ligase complex and is mostly driven to proteasomal degradation. 38,39 PP2A dephosphorylates MCL1 and prevents interaction between MCL1 and the complex.…”

Section: Discussionmentioning

confidence: 99%

“…38,39 Phosphorylated MCL1 can be an easy target of an E3 ubiquitin ligase complex and is mostly driven to proteasomal degradation. 38,39 PP2A dephosphorylates MCL1 and prevents interaction between MCL1 and the complex. 38,39 A previous study showed that PP2A inhibition dramatically decreased the protein levels of MCL1 within 2 h in Burkitt lymphoma cells.…”

Section: Discussionmentioning

confidence: 99%

“…38,39 PP2A dephosphorylates MCL1 and prevents interaction between MCL1 and the complex. 38,39 A previous study showed that PP2A inhibition dramatically decreased the protein levels of MCL1 within 2 h in Burkitt lymphoma cells. 39 Although we confirmed that PP2A B56α is bound to MCL1 in both Karpas231 and OCI-Ly8 cells, the association was unchanged after exposure to venetoclax ( data not shown ).…”

Section: Discussionmentioning

confidence: 99%

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Targeting BCL2 with venetoclax is a promising therapeutic strategy for “double-proteinexpression” lymphoma with MYC and BCL2 rearrangements

et al. 2018

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The so-called “double-hit” and “double-protein-expression” lymphoma with MYC and BCL2 rearrangements is a rare, mature B-cell neoplasm characterized by a germinal center B-cell phenotype, abundant protein expression of MYC and BCL2, rapid disease progression, and a poor prognosis. In this study, we showed the potential benefit of the BCL2 inhibitor venetoclax in the treatment of this disease. Immunohistochemical studies of the lymphoma tissues confirmed that overexpression of MYC and BCL2 was observed more frequently in this subtype than in other germinal center B-cell-like diffuse large B-cell lymphomas. In contrast, another pro-survival protein MCL1 was less expressed in this subtype, even when compared with its expression in the non-“double-hit” and “double-protein-expression” type. Furthermore, in vitro studies using two “double-hit” and “double-protein-expression” lymphoma-derived cell lines, Karpas231 and OCI-Ly8, clearly showed that a low concentration of venetoclax, but not the MCL1 inhibitor S63845, was sufficient to induce apoptosis in the two lines, compared with in other germinal center B-cell-derived cell lines, BJAB and SU-DHL10. These results indicate that the survival of this type of lymphoma depends predominantly on BCL2 rather than on MCL1. Unexpectedly, we found that venetoclax not only disrupts the interaction between BCL2 and the pro-apoptotic protein BIM, but also leads to dephosphorylation of BCL2 and further downregulates MCL1 protein expression, probably through modulation of the protein phosphatase 2A B56α activity in Karpas231 and OCI-Ly8. Indeed, a low concentration of venetoclax induced substantial apoptosis in the primary lymphoma cells, regardless of high protein expression of MCL1 associated with venetoclax resistance. Venetoclax clearly triggers the signal transduction related to BCL2 and MCL1 in “double-hit” and “double-protein-expression” lymphoma cells.

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“…In this study, mass spectrometry analysis of IL-2R␤ revealed that Thr-450 is phosphorylated following CA treatment (data not shown). Interestingly, ERK1/2 can become activated by CA-induced inhibition of PP1 and PP2A (39). To delineate the kinetics of PP1 and PP2A inhibition on Thr-450 phosphorylation, YT cells were treated with 100 nM CA for 0 -60 min.…”

Section: Pp1 But Not Pp2a Negatively Regulates Phosphorylation Of Il-mentioning

confidence: 99%

Interleukin-2 Receptor β Thr-450 Phosphorylation Is a Positive Regulator for Receptor Complex Stability and Activation of Signaling Molecules

Ruiz-Medina

Ross

Kirken

2015

Journal of Biological Chemistry

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Background: IL-2 signaling occurs by cognate receptor phosphorylation, ultimately resulting in regulation of lymphocyte function. Results: IL-2R␤ Thr(P)-450 positively regulates receptor complex stability and downstream STAT5 transcriptional activity. Conclusion: IL-2R␤ Thr-450 is a novel ERK1/2-mediated phosphoregulatory site important for optimal IL-2 signal transduction. Significance: IL-2R␤ threonine phosphorylation governs IL-2 signal transduction and may play a role in immune cell dysfunction.

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Inhibition of Protein Phosphatase 2A (PP2A) Prevents Mcl-1 Protein Dephosphorylation at the Thr-163/Ser-159 Phosphodegron, Dramatically Reducing Expression in Mcl-1-amplified Lymphoma Cells

Abstract: Background: Although Mcl-1 is normally subject to rapid turnover via a phosphodegron at Thr-163/Ser-159 and other pathways, sustained expression promotes viability/chemoresistance in cancer cells.

Cited by 16 publications

References 70 publications

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

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

Targeting BCL2 with venetoclax is a promising therapeutic strategy for “double-proteinexpression” lymphoma with MYC and BCL2 rearrangements

Interleukin-2 Receptor β Thr-450 Phosphorylation Is a Positive Regulator for Receptor Complex Stability and Activation of Signaling Molecules

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