Inactivation of CK1α in multiple myeloma empowers drug cytotoxicity by affecting AKT and β-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

doi:10.18632/oncotarget.14654

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

Oncotarget. 2017 Feb 28;8(9):14604-14619. doi: 10.18632/oncotarget.14654.

Authors

Sabrina Manni^{1

2}, Marilena Carrino^{1

2}, Martina Manzoni^{3

4}, Ketty Gianesin^{1

2}, Sara Canovas Nunes^{1

2}, Matteo Costacurta^{1

2}, Laura Quotti Tubi^{1

2}, Paolo Macaccaro^{1

2}, Elisa Taiana^{3

4}, Anna Cabrelle², Gregorio Barilà^{1

2}, Annalisa Martines⁵, Renato Zambello^{1

2}, Laura Bonaldi⁵, Livio Trentin^{1

2}, Antonino Neri^{3

4}, Gianpietro Semenzato^{1

2}, Francesco Piazza^{1

2}

Affiliations

¹ Department of Medicine, Hematology and Clinical Immunology Section, University of Padova, Padova, Italy.
² Venetian Institute of Molecular Medicine, Padova, Italy.
³ Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy.
⁴ Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
⁵ Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS- Padova, Italy.

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.

Keywords: CK1α; lenalidomide; multiple myeloma.

MeSH terms

Adult
Aged
Aged, 80 and over
Antineoplastic Agents / pharmacology
Bortezomib / pharmacology
Casein Kinase I / genetics*
Casein Kinase I / metabolism
Cell Line
Cell Line, Tumor
Cell Survival / drug effects
Cell Survival / genetics
Cells, Cultured
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Lenalidomide
Male
Middle Aged
Multiple Myeloma / genetics*
Multiple Myeloma / metabolism
Multiple Myeloma / pathology
Proto-Oncogene Proteins c-akt / genetics*
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins c-mdm2 / genetics
Proto-Oncogene Proteins c-mdm2 / metabolism
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects
Signal Transduction / genetics*
Thalidomide / analogs & derivatives
Thalidomide / pharmacology
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
beta Catenin / genetics*
beta Catenin / metabolism

Substances

Antineoplastic Agents
Cyclin-Dependent Kinase Inhibitor p21
Tumor Suppressor Protein p53
beta Catenin
Thalidomide
Bortezomib
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
Casein Kinase I
Proto-Oncogene Proteins c-akt
Lenalidomide