Research Papers:
Inactivation of CK1α in multiple myeloma empowers drug cytotoxicity by affecting AKT and β-catenin survival signaling pathways
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Abstract
Sabrina Manni1,2, Marilena Carrino1,2, Martina Manzoni3,4, Ketty Gianesin1,2, Sara Canovas Nunes1,2, Matteo Costacurta1,2, Laura Quotti Tubi1,2, Paolo Macaccaro1,2, Elisa Taiana3,4, Anna Cabrelle2, Gregorio Barilà1,2, Annalisa Martines5, Renato Zambello1,2, Laura Bonaldi5, Livio Trentin1,2, Antonino Neri3,4, Gianpietro Semenzato1,2, Francesco Piazza1,2
1Department of Medicine, Hematology and Clinical Immunology Section, University of Padova, Padova, Italy
2Venetian Institute of Molecular Medicine, Padova, Italy
3Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy
4Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
5Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS- Padova, Italy
Correspondence to:
Sabrina Manni, email: [email protected]
Francesco Piazza, email: [email protected]
Keywords: CK1α, multiple myeloma, lenalidomide
Received: September 07, 2016 Accepted: January 07, 2017 Published: January 14, 2017
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 β-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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