title: Inactivation of CK1α in multiple myeloma empowers drug cytotoxicity by affecting AKT and β-catenin survival signaling pathways.
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.
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Padova, Padova, Italy.|Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Manni
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Padova, Padova, Italy.|Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Carrino
authors.affiliation: Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy.|Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Manzoni
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Padova, Padova, Italy.|Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Ketty
authors.initials: K
authors.lastname: Gianesin
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Padova, Padova, Italy.|Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Sara Canovas
authors.initials: SC
authors.lastname: Nunes
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Padova, Padova, Italy.|Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Costacurta
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Padova, Padova, Italy.|Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Laura Quotti
authors.initials: LQ
authors.lastname: Tubi
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Padova, Padova, Italy.|Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Macaccaro
authors.affiliation: Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy.|Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Taiana
authors.affiliation: Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Cabrelle
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Padova, Padova, Italy.|Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Gregorio
authors.initials: G
authors.lastname: Barilà
authors.affiliation: Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS- Padova, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Martines
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Padova, Padova, Italy.|Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Zambello
authors.affiliation: Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS- Padova, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Bonaldi
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Padova, Padova, Italy.|Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Trentin
authors.affiliation: Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy.|Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Padova, Padova, Italy.|Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Semenzato
authors.affiliation: Department of Medicine, Hematology and Clinical Immunology Section, University of Padova, Padova, Italy.|Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Piazza
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D000069286:Bortezomib / Q000494:pharmacology; D047389:Casein Kinase I / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D013792:Thalidomide; D000069286:Bortezomib; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D047389:Casein Kinase I; D051057:Proto-Oncogene Proteins c-akt; D000077269:Lenalidomide
keywords: CK1α; lenalidomide; multiple myeloma