Inactivation of CK1α in multiple myeloma empowers drug cytotoxicity by affecting AKT and ß-catenin survival signaling pathways

Sabrina Manni, Marilena Carrino, Martina Manzoni, Ketty Gianesin, Sara Canovas Nunes, Matteo Costacurta, Laura Quotti Tubi, Paolo Macaccaro, Elisa Taiana, Anna Cabrelle, Gregorio Barilà, Annalisa Martines, Renato Zambello, Laura Bonaldi, Livio Trentin, Antonino Neri, Gianpietro Semenzato, Francesco Piazza

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Recent evidence indicates that protein kinase CK1α may support the growth of multiple myeloma (MM) plasma cells. Here, by analyzing a large cohort of MM cases, we found that high CK1α mRNA levels are virtually associated with all MM patients. Moreover, we provided functional evidence that CK1α activity is essential for malignant plasma cell survival even in the protective niche generated by co-cultures with bone marrow stromal cells. We demonstrated that CK1α inactivation, while toxic for myeloma cells, is dispensable for the survival of healthy B lymphocytes and stromal cells. Disruption of CK1α function in myeloma cells resulted in decreased Mdm2, increased p53 and p21 and reduced expression of ß-catenin and AKT. These effects were mediated partially by p53 and caspase activity. Finally, we discovered that CK1α inactivation enhanced the cytotoxic effect of both bortezomib and lenalidomide. Overall, our study supports a role for CK1α as a potential therapeutic target in MM in combination with proteasome inhibitors and/or immunomodulatory drugs.

Original languageEnglish
Pages (from-to)14604-14619
Number of pages16
JournalOncotarget
Volume8
Issue number9
DOIs
Publication statusPublished - 2017

Fingerprint

Catenins
Multiple Myeloma
Survival
Plasma Cells
Pharmaceutical Preparations
Casein Kinase I
Proteasome Inhibitors
Poisons
Stromal Cells
Caspases
Coculture Techniques
Mesenchymal Stromal Cells
Cell Survival
B-Lymphocytes
Messenger RNA
Growth
Therapeutics

Keywords

  • CK1α
  • Lenalidomide
  • Multiple myeloma

ASJC Scopus subject areas

  • Oncology

Cite this

Manni, S., Carrino, M., Manzoni, M., Gianesin, K., Nunes, S. C., Costacurta, M., ... Piazza, F. (2017). Inactivation of CK1α in multiple myeloma empowers drug cytotoxicity by affecting AKT and ß-catenin survival signaling pathways. Oncotarget, 8(9), 14604-14619. https://doi.org/10.18632/oncotarget.14654

Inactivation of CK1α in multiple myeloma empowers drug cytotoxicity by affecting AKT and ß-catenin survival signaling pathways. / Manni, Sabrina; Carrino, Marilena; Manzoni, Martina; Gianesin, Ketty; Nunes, Sara Canovas; Costacurta, Matteo; Tubi, Laura Quotti; Macaccaro, Paolo; Taiana, Elisa; Cabrelle, Anna; Barilà, Gregorio; Martines, Annalisa; Zambello, Renato; Bonaldi, Laura; Trentin, Livio; Neri, Antonino; Semenzato, Gianpietro; Piazza, Francesco.

In: Oncotarget, Vol. 8, No. 9, 2017, p. 14604-14619.

Research output: Contribution to journalArticle

Manni, S, Carrino, M, Manzoni, M, Gianesin, K, Nunes, SC, Costacurta, M, Tubi, LQ, Macaccaro, P, Taiana, E, Cabrelle, A, Barilà, G, Martines, A, Zambello, R, Bonaldi, L, Trentin, L, Neri, A, Semenzato, G & Piazza, F 2017, 'Inactivation of CK1α in multiple myeloma empowers drug cytotoxicity by affecting AKT and ß-catenin survival signaling pathways', Oncotarget, vol. 8, no. 9, pp. 14604-14619. https://doi.org/10.18632/oncotarget.14654
Manni, Sabrina ; Carrino, Marilena ; Manzoni, Martina ; Gianesin, Ketty ; Nunes, Sara Canovas ; Costacurta, Matteo ; Tubi, Laura Quotti ; Macaccaro, Paolo ; Taiana, Elisa ; Cabrelle, Anna ; Barilà, Gregorio ; Martines, Annalisa ; Zambello, Renato ; Bonaldi, Laura ; Trentin, Livio ; Neri, Antonino ; Semenzato, Gianpietro ; Piazza, Francesco. / Inactivation of CK1α in multiple myeloma empowers drug cytotoxicity by affecting AKT and ß-catenin survival signaling pathways. In: Oncotarget. 2017 ; Vol. 8, No. 9. pp. 14604-14619.
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abstract = "Recent evidence indicates that protein kinase CK1α may support the growth of multiple myeloma (MM) plasma cells. Here, by analyzing a large cohort of MM cases, we found that high CK1α mRNA levels are virtually associated with all MM patients. Moreover, we provided functional evidence that CK1α activity is essential for malignant plasma cell survival even in the protective niche generated by co-cultures with bone marrow stromal cells. We demonstrated that CK1α inactivation, while toxic for myeloma cells, is dispensable for the survival of healthy B lymphocytes and stromal cells. Disruption of CK1α function in myeloma cells resulted in decreased Mdm2, increased p53 and p21 and reduced expression of {\ss}-catenin and AKT. These effects were mediated partially by p53 and caspase activity. Finally, we discovered that CK1α inactivation enhanced the cytotoxic effect of both bortezomib and lenalidomide. Overall, our study supports a role for CK1α as a potential therapeutic target in MM in combination with proteasome inhibitors and/or immunomodulatory drugs.",
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