Protein Kinase CK1α Sustains B-Cell Receptor Signaling in Mantle Cell Lymphoma
Mantle Cell Lymphoma (MCL) is still an incurable B-cell malignancy characterized by poor prognosis and frequent relapses. B Cell Receptor (BCR) signaling inhibitors, in particular of the kinases BTK and PI3Kγ/δ, have demonstrated clinically meaningful anti-proliferative effects in B cell tumors. How...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.733848/full |
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| author | Sabrina Manni Sabrina Manni Anna Fregnani Anna Fregnani Laura Quotti Tubi Laura Quotti Tubi Zaira Spinello Zaira Spinello Marco Carraro Marco Carraro Greta Scapinello Greta Scapinello Andrea Visentin Andrea Visentin Gregorio Barilà Gregorio Barilà Marco Pizzi Angelo Paolo Dei Tos Fabrizio Vianello Renato Zambello Renato Zambello Carmela Gurrieri Carmela Gurrieri Gianpietro Semenzato Gianpietro Semenzato Livio Trentin Livio Trentin Francesco Piazza Francesco Piazza |
| author_facet | Sabrina Manni Sabrina Manni Anna Fregnani Anna Fregnani Laura Quotti Tubi Laura Quotti Tubi Zaira Spinello Zaira Spinello Marco Carraro Marco Carraro Greta Scapinello Greta Scapinello Andrea Visentin Andrea Visentin Gregorio Barilà Gregorio Barilà Marco Pizzi Angelo Paolo Dei Tos Fabrizio Vianello Renato Zambello Renato Zambello Carmela Gurrieri Carmela Gurrieri Gianpietro Semenzato Gianpietro Semenzato Livio Trentin Livio Trentin Francesco Piazza Francesco Piazza |
| author_sort | Sabrina Manni |
| collection | DOAJ |
| description | Mantle Cell Lymphoma (MCL) is still an incurable B-cell malignancy characterized by poor prognosis and frequent relapses. B Cell Receptor (BCR) signaling inhibitors, in particular of the kinases BTK and PI3Kγ/δ, have demonstrated clinically meaningful anti-proliferative effects in B cell tumors. However, refractoriness to these drugs may develop, portending a dismal prognosis. Protein kinase CK1α is an emerging pro-growth enzyme in B cell malignancies. In multiple myeloma, this kinase sustains β-catenin and AKT-dependent survival and is involved in the activation of NF-κB in B cells. In this study, we analyzed the role of CK1α on MCL cell survival and proliferation, on the regulation of BCR-related BTK, NF-κB, PI3K/AKT signaling cascades and the effects of CK1α chemical inhibition or gene silencing in association with the BTK inhibitor Ibrutinib or the PI3Kγ/δ inhibitor Duvelisib. CK1α was found highly expressed in MCL cells as compared to normal B cells. The inactivation/loss of CK1α caused MCL cell apoptosis and proliferation arrest. CK1α sustained BCR signaling, in particular the NF-κB, AKT and BTK pathways by modulating the phosphorylation of Ser 652 on CARD11, Ser 536 p65 on NF-κB, Ser 473 on AKT, Tyr 223 on BTK, as well as the protein levels. We also provided evidence that CK1α-mediated regulation of CARD11 and BTK likely implicates a physical interaction. The combination of CK1α inhibition with Ibrutinib or Duvelisib synergistically increased cytotoxicity, leading to a further decrease of the activation of BCR signaling pathways. Therefore, CK1α sustains MCL growth through the regulation of BCR-linked survival signaling cascades and protects from Ibrutinib/Duvelisib-induced apoptosis. Thus, CK1α could be considered as a rational molecular target for the treatment of MCL, in association with novel agents. |
| first_indexed | 2024-12-22T14:39:58Z |
| format | Article |
| id | doaj.art-c56d9b095bbc411ca2589e2e8f63ba58 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-22T14:39:58Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-c56d9b095bbc411ca2589e2e8f63ba582022-12-21T18:22:35ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-10-011110.3389/fonc.2021.733848733848Protein Kinase CK1α Sustains B-Cell Receptor Signaling in Mantle Cell LymphomaSabrina Manni0Sabrina Manni1Anna Fregnani2Anna Fregnani3Laura Quotti Tubi4Laura Quotti Tubi5Zaira Spinello6Zaira Spinello7Marco Carraro8Marco Carraro9Greta Scapinello10Greta Scapinello11Andrea Visentin12Andrea Visentin13Gregorio Barilà14Gregorio Barilà15Marco Pizzi16Angelo Paolo Dei Tos17Fabrizio Vianello18Renato Zambello19Renato Zambello20Carmela Gurrieri21Carmela Gurrieri22Gianpietro Semenzato23Gianpietro Semenzato24Livio Trentin25Livio Trentin26Francesco Piazza27Francesco Piazza28Department of Medicine-DIMED, Hematology and Clinical Immunology Section, University of Padova, Padova, ItalyLaboratory of Myeloma and Lymphoma Pathobiology, Veneto Institute of Molecular Medicine, Padova, ItalyDepartment of Medicine-DIMED, Hematology and Clinical Immunology Section, University of Padova, Padova, ItalyLaboratory of Myeloma and Lymphoma Pathobiology, Veneto Institute of Molecular Medicine, Padova, ItalyDepartment of Medicine-DIMED, Hematology and Clinical Immunology Section, University of Padova, Padova, ItalyLaboratory of Myeloma and Lymphoma Pathobiology, Veneto Institute of Molecular Medicine, Padova, ItalyDepartment of Medicine-DIMED, Hematology and Clinical Immunology Section, University of Padova, Padova, ItalyLaboratory of Myeloma and Lymphoma Pathobiology, Veneto Institute of Molecular Medicine, Padova, ItalyDepartment of Medicine-DIMED, Hematology and Clinical Immunology Section, University of Padova, Padova, ItalyLaboratory of Myeloma and Lymphoma Pathobiology, Veneto Institute of Molecular Medicine, Padova, ItalyDepartment of Medicine-DIMED, Hematology and Clinical Immunology Section, University of Padova, Padova, ItalyLaboratory of Myeloma and Lymphoma Pathobiology, Veneto Institute of Molecular Medicine, Padova, ItalyDepartment of Medicine-DIMED, Hematology and Clinical Immunology Section, University of Padova, Padova, ItalyLaboratory of Myeloma and Lymphoma Pathobiology, Veneto Institute of Molecular Medicine, Padova, ItalyDepartment of Medicine-DIMED, Hematology and Clinical Immunology Section, University of Padova, Padova, ItalyLaboratory of Myeloma and Lymphoma Pathobiology, Veneto Institute of Molecular Medicine, Padova, ItalyDepartment of Medicine-DIMED, Surgical Pathology and Cytopathology Unit, University of Padova, Padova, ItalyDepartment of Medicine-DIMED, Surgical Pathology and Cytopathology Unit, University of Padova, Padova, ItalyDepartment of Medicine-DIMED, Hematology and Clinical Immunology Section, University of Padova, Padova, ItalyDepartment of Medicine-DIMED, Hematology and Clinical Immunology Section, University of Padova, Padova, ItalyLaboratory of Myeloma and Lymphoma Pathobiology, Veneto Institute of Molecular Medicine, Padova, ItalyDepartment of Medicine-DIMED, Hematology and Clinical Immunology Section, University of Padova, Padova, ItalyLaboratory of Myeloma and Lymphoma Pathobiology, Veneto Institute of Molecular Medicine, Padova, ItalyDepartment of Medicine-DIMED, Hematology and Clinical Immunology Section, University of Padova, Padova, ItalyLaboratory of Myeloma and Lymphoma Pathobiology, Veneto Institute of Molecular Medicine, Padova, ItalyDepartment of Medicine-DIMED, Hematology and Clinical Immunology Section, University of Padova, Padova, ItalyLaboratory of Myeloma and Lymphoma Pathobiology, Veneto Institute of Molecular Medicine, Padova, ItalyDepartment of Medicine-DIMED, Hematology and Clinical Immunology Section, University of Padova, Padova, ItalyLaboratory of Myeloma and Lymphoma Pathobiology, Veneto Institute of Molecular Medicine, Padova, ItalyMantle Cell Lymphoma (MCL) is still an incurable B-cell malignancy characterized by poor prognosis and frequent relapses. B Cell Receptor (BCR) signaling inhibitors, in particular of the kinases BTK and PI3Kγ/δ, have demonstrated clinically meaningful anti-proliferative effects in B cell tumors. However, refractoriness to these drugs may develop, portending a dismal prognosis. Protein kinase CK1α is an emerging pro-growth enzyme in B cell malignancies. In multiple myeloma, this kinase sustains β-catenin and AKT-dependent survival and is involved in the activation of NF-κB in B cells. In this study, we analyzed the role of CK1α on MCL cell survival and proliferation, on the regulation of BCR-related BTK, NF-κB, PI3K/AKT signaling cascades and the effects of CK1α chemical inhibition or gene silencing in association with the BTK inhibitor Ibrutinib or the PI3Kγ/δ inhibitor Duvelisib. CK1α was found highly expressed in MCL cells as compared to normal B cells. The inactivation/loss of CK1α caused MCL cell apoptosis and proliferation arrest. CK1α sustained BCR signaling, in particular the NF-κB, AKT and BTK pathways by modulating the phosphorylation of Ser 652 on CARD11, Ser 536 p65 on NF-κB, Ser 473 on AKT, Tyr 223 on BTK, as well as the protein levels. We also provided evidence that CK1α-mediated regulation of CARD11 and BTK likely implicates a physical interaction. The combination of CK1α inhibition with Ibrutinib or Duvelisib synergistically increased cytotoxicity, leading to a further decrease of the activation of BCR signaling pathways. Therefore, CK1α sustains MCL growth through the regulation of BCR-linked survival signaling cascades and protects from Ibrutinib/Duvelisib-induced apoptosis. Thus, CK1α could be considered as a rational molecular target for the treatment of MCL, in association with novel agents.https://www.frontiersin.org/articles/10.3389/fonc.2021.733848/fullmantle cell lymphomaCK1αBCR inhibitorsibrutinibduvelisibtargeted therapy |
| spellingShingle | Sabrina Manni Sabrina Manni Anna Fregnani Anna Fregnani Laura Quotti Tubi Laura Quotti Tubi Zaira Spinello Zaira Spinello Marco Carraro Marco Carraro Greta Scapinello Greta Scapinello Andrea Visentin Andrea Visentin Gregorio Barilà Gregorio Barilà Marco Pizzi Angelo Paolo Dei Tos Fabrizio Vianello Renato Zambello Renato Zambello Carmela Gurrieri Carmela Gurrieri Gianpietro Semenzato Gianpietro Semenzato Livio Trentin Livio Trentin Francesco Piazza Francesco Piazza Protein Kinase CK1α Sustains B-Cell Receptor Signaling in Mantle Cell Lymphoma Frontiers in Oncology mantle cell lymphoma CK1α BCR inhibitors ibrutinib duvelisib targeted therapy |
| title | Protein Kinase CK1α Sustains B-Cell Receptor Signaling in Mantle Cell Lymphoma |
| title_full | Protein Kinase CK1α Sustains B-Cell Receptor Signaling in Mantle Cell Lymphoma |
| title_fullStr | Protein Kinase CK1α Sustains B-Cell Receptor Signaling in Mantle Cell Lymphoma |
| title_full_unstemmed | Protein Kinase CK1α Sustains B-Cell Receptor Signaling in Mantle Cell Lymphoma |
| title_short | Protein Kinase CK1α Sustains B-Cell Receptor Signaling in Mantle Cell Lymphoma |
| title_sort | protein kinase ck1α sustains b cell receptor signaling in mantle cell lymphoma |
| topic | mantle cell lymphoma CK1α BCR inhibitors ibrutinib duvelisib targeted therapy |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.733848/full |
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