Novel players in multiple myeloma pathogenesis: Role of protein kinases CK2 and GSK3

Abstract

Multiple myeloma (MM) is an incurable plasma cell malignancy, which causes a significant morbidity due to organ damage and bone tissue destruction. In recent years, novel drugs have become available for MM therapy thanks to a more deepened knowledge of this disease's pathogenesis. The perspective of employing targeted therapies has considerably changed the expectations on the clinical outcome for patients affected by this malignancy and among the targetable molecules identified for MM therapy are several protein kinases, which have been proven to play relevant roles in supporting malignant plasma cell growth by regulating critical signaling cascades and by sustaining oncogenic mechanisms. Protein kinase CK2 (formerly known as casein kinase 2) and GSK3 (glycogen synthase kinase 3) are two multifaceted serine-threonine kinases whose task in the pathogenesis of malignant cell growth is increasingly emerging both in solid and blood tumors. In hematologic malignancies, CK2 and GSK3 have been shown to play an oncogenic function in chronic and acute leukemias as well as in MM. They have been demonstrated to act by impinging on pivotal signaling pathways that control malignant clone growth. We will herein briefly review the more recent advancements on the role of these two kinases in regulating the NF-κB, STAT3 and endoplasmic reticulum (ER) stress/unfolded protein response (UPR) signaling in MM and discuss the rationale of using small selective inhibitors as a therapeutic strategy to hamper the growth of malignant plasma cells or to improve the MM-associated bone disease.

Introduction

Multiple myeloma (MM) is a blood tumor arising from terminally differentiated B lymphocytes, plasma cells, which grow mainly in the bone marrow (BM). Due to the progressive accumulation of malignant plasma cells, which produce monoclonal immunoglobulins or parts of them (light chains), end-organ damage often occurs in the bone, in the kidneys and in the bone marrow [1].

Although MM is a fatal disorder, in recent years notable progresses have been achieved in the cure of this disease, mostly due to the introduction of novel and effective drugs in the therapeutic armamentarium. For instance, the discovery that proteasome inhibitors and immunomodulatory drugs (iMIDs) caused MM cell growth arrest and their subsequent clinical employment have changed the clinical outcome of MM patients allowing to obtain a prolongation of the overall survival.

Significant efforts are being carried out in order to identify the cellular and molecular alterations underlying MM pathogenesis. As a consequence, several pre-clinical studies as well as clinical trials have started with the aim of identifying more effective therapeutic combinations able to arrest MM cell growth [2], [3].

It is now well established that malignant plasma cell growth relies on cell intrinsic as well as cell extrinsic or external mechanisms. Since specific genetic lesions are associated with the deregulation of signaling pathways in MM plasma cells [4], based on their characterization it is now possible to prognostically classify MM patients [5]. Overall, a central importance in MM pathogenesis is displayed by perturbations of signaling cascades regulating the balance between cell death and life. For instance, the deregulation of Cyclin Ds, mostly D1 but also D2 and D3, is associated with a specific chromosomal translocation t(11;14) and/or specific genomic alterations. Cyclin Ds over-expression leads to increased cell cycle progression and proliferation. Also, the transcription factors c-Myc is deregulated in a substantial fraction of MM and it seems that malignant plasma cells are addicted to c-Myc over-function. Last, the NF-κB transcription factor signaling pathway is disrupted in approximately 20% of MM cases. Different kind of mutations affecting NF-κB regulating genes altogether may converge on the over-activation of this pro-survival signaling cascade [6].

Another very important pathogenic role is played by the MM microenvironment. In the BM malignant plasma cells take crucial interactions with surrounding hematopoietic and non-hematopoietic (stromal) cells as well as with the extracellular matrix. Contacts between MM cells and the microenvironment support MM cell growth and provide a protective niche against cytotoxic agents. It is increasingly clear that the MM BM microenvironment exhibits distinct alterations, which concur to provide an inflammatory/proangiogenic milieu that in turn favors malignant plasma cell growth [5], [7].

On the way to search for molecules involved in sustaining MM cell growth others’ and our group analyzed the function of two serine-threonine protein kinases, CK2 and GSK3 in MM. These PKs are ubiquitous, regulate several cellular processes and their loss in mice is lethal.

CK2 is mostly a constitutively active kinase, even though also inducible, mainly by stress signals; GSK3, originally identified in the insulin-dependent signaling pathway as the kinase phosphorylating the enzyme glycogen synthase, is a constitutively active kinase, which is shut off in a signal-dependent fashion by upstream cascades, in particular by the PI3K/AKT axis [8], [9].

CK2 and GSK3 share a common feature, i.e. the ability to phosphorylate several transcription factors, many of which are involved in cell proliferation, differentiation and apoptosis. For instance, both CK2 and GSK3 can phosphorylate NF-κB cascade members, promoting the activation of this pathway [10]. CK2 and GSK3 also phosphorylate c-Myc and Myb, causing an increased activity of these transcription factors [11], [12]. CK2 and GSK3 have also been involved in the function of several developmentally regulated hematopoietic-specific transcription factors and chromatin modifiers [13].

Recently, a number of studies have described that both these PKs can promote MM plasma cell growth by affecting critical signaling pathways and cellular mechanisms. We will herein review the current knowledge on the pathogenic roles of CK2 and GSK3 in MM and discuss the possibility of using small selective CK2 and GSK3 inhibitors as therapeutic agents in the treatment of this disease.