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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...

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Autores principales: Manni, Sabrina, Fregnani, Anna, Quotti Tubi, Laura, Spinello, Zaira, Carraro, Marco, Scapinello, Greta, Visentin, Andrea, Barilà, Gregorio, Pizzi, Marco, Dei Tos, Angelo Paolo, Vianello, Fabrizio, Zambello, Renato, Gurrieri, Carmela, Semenzato, Gianpietro, Trentin, Livio, Piazza, Francesco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551451/
https://www.ncbi.nlm.nih.gov/pubmed/34722279
http://dx.doi.org/10.3389/fonc.2021.733848
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author Manni, Sabrina
Fregnani, Anna
Quotti Tubi, Laura
Spinello, Zaira
Carraro, Marco
Scapinello, Greta
Visentin, Andrea
Barilà, Gregorio
Pizzi, Marco
Dei Tos, Angelo Paolo
Vianello, Fabrizio
Zambello, Renato
Gurrieri, Carmela
Semenzato, Gianpietro
Trentin, Livio
Piazza, Francesco
author_facet Manni, Sabrina
Fregnani, Anna
Quotti Tubi, Laura
Spinello, Zaira
Carraro, Marco
Scapinello, Greta
Visentin, Andrea
Barilà, Gregorio
Pizzi, Marco
Dei Tos, Angelo Paolo
Vianello, Fabrizio
Zambello, Renato
Gurrieri, Carmela
Semenzato, Gianpietro
Trentin, Livio
Piazza, Francesco
author_sort Manni, Sabrina
collection PubMed
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.
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spelling pubmed-85514512021-10-29 Protein Kinase CK1α Sustains B-Cell Receptor Signaling in Mantle Cell Lymphoma Manni, Sabrina Fregnani, Anna Quotti Tubi, Laura Spinello, Zaira Carraro, Marco Scapinello, Greta Visentin, Andrea Barilà, Gregorio Pizzi, Marco Dei Tos, Angelo Paolo Vianello, Fabrizio Zambello, Renato Gurrieri, Carmela Semenzato, Gianpietro Trentin, Livio Piazza, Francesco Front Oncol Oncology 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. Frontiers Media S.A. 2021-10-14 /pmc/articles/PMC8551451/ /pubmed/34722279 http://dx.doi.org/10.3389/fonc.2021.733848 Text en Copyright © 2021 Manni, Fregnani, Quotti Tubi, Spinello, Carraro, Scapinello, Visentin, Barilà, Pizzi, Dei Tos, Vianello, Zambello, Gurrieri, Semenzato, Trentin and Piazza https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Manni, Sabrina
Fregnani, Anna
Quotti Tubi, Laura
Spinello, Zaira
Carraro, Marco
Scapinello, Greta
Visentin, Andrea
Barilà, Gregorio
Pizzi, Marco
Dei Tos, Angelo Paolo
Vianello, Fabrizio
Zambello, Renato
Gurrieri, Carmela
Semenzato, Gianpietro
Trentin, Livio
Piazza, Francesco
Protein Kinase CK1α Sustains B-Cell Receptor Signaling in Mantle Cell Lymphoma
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 Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551451/
https://www.ncbi.nlm.nih.gov/pubmed/34722279
http://dx.doi.org/10.3389/fonc.2021.733848
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