Aurora kinase A is a target of Wnt/β-catenin involved in multiple myeloma disease progression

Abstract

Multiple myeloma (MM) is a cancer of plasma cells with complex molecular characteristics that evolves from monoclonal gammopathy of undetermined significance, a highly prevalent premalignant condition. MM is the second most frequent hematologic cancer in the United States, and it remains incurable, thereby highlighting the need for new therapeutic approaches, particularly those targeting common molecular pathways involved in disease progression and maintenance, shared across different MM subtypes. Here we report that Wnt/␤-catenin is one such pathway. We document the involvement of ␤-catenin in cell-cycle regulation, proliferation, and invasion contributing to enhanced proliferative and metastatic properties of MM. The pleiotropic effects of ␤-catenin in MM correlate with its transcriptional function, and we demonstrate regulation of a novel target gene, Aurora kinase A, implicating ␤-catenin in G2/M regulation. ␤-catenin and Aurora kinase A are present in most MM but not in normal plasma cells and are expressed in a pattern that parallels progression from monoclonal gammopathy of undetermined significance to MM. Our data provide evidence for a novel functional link between ␤-catenin and Aurora kinase A, underscoring a critical role of these pathways in MM disease progression. (Blood. 2009;114:2699-2708) IntroductionMultiple myeloma (MM) is a neoplasm of plasma cells that infiltrates the bone marrow (BM). Despite recent advances in its treatment, it remains incurable, with a median survival of 6 years. 1 MM accounts for more than 10% of all hematologic malignancies and is the second most frequent hematologic cancer in the United States. It is typically preceded by an age-progressive condition termed monoclonal gammopathy of undetermined significance (MGUS), which is present in 1% to 10% of adults older than 25 years of age and progresses to malignant MM at a rate of 0.5% to 3% annually. 1,2 This disease is characterized by frequent chromosomal aberrations and mutations in several oncogenes and tumor-suppressor genes. 3,4 The Wnt/␤-catenin pathway is significant in cancer development because numerous human malignancies such as colorectal, hepatocellular, and breast cancer harbor activating mutations in critical components of this pathway. 5,6 Normally, the Wnt signaling pathway is active during embryogenesis, hematopoietic stem cell growth, cell differentiation, and tissue development. ␤-catenin, a central effector of the Wnt pathway, is involved in both nuclear and cytoplasmic functions. 7,8 In the absence of Wnt ligands, ␤-catenin is targeted by a complex consisting of adenomatous polyposis coli, axin, glycogen synthase kinase-3␤, and casein kinase 1␣ that phosphorylate and mark it for degradation by the ubiquitinproteasome pathway. 9,10 Upon Wnt stimulation, however, the kinase complex is dissociated, and ␤-catenin is not targeted for destruction. The active form of ␤-catenin translocates to the nucleus and, in association with lymphoid enhancer factor (LEF)/Tcell factor (TCF) proteins, activates transcription...

Natural killer cell lymphoma shares strikingly similar molecular features with a group of non-hepatosplenic γδ T-cell lymphoma and is highly sensitive to a novel aurora kinase A inhibitor in vitro

“…34 It also upregulates MYC and telomerase activity 32 and promotes WNT signaling. 33 Some of these signatures were significantly enriched in NKCL (Table 3). AURKA is also located at a frequently amplified locus (20q13) in NK-cell lymphoma.…”

“…The expression of the protein was seen in all NK-lymphoma cell lines (Figure 4b and c). AURKA is located at a frequently (450%) amplified locus (20q13) in lymphomas derived from NKCL 31 and is involved in multiple pathways, promoting the proliferative function of MYC 32 and WNT signaling, 33 while inhibiting TP53. 34 Moreover, AURKA is upregulated by hypoxia 35 that is frequently observed in ENKTL.…”

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

“…On the basis of these articles, we propose that PKCd would modulate Mcl-1 by regulation of the Wnt/b-catenin pathway in prostate cancer cells. The Wnt/b-catenin pathway regulates embryogenesis, proliferation, cell differentiation, or migration, and it is abnormally activated in different tumor types (18,20,23,24,28,29). b-catenin is a strongly regulated factor with a central role in this pathway.…”

“…In the absence of Wnt activation, a degradation complex formed by GSK3b between other proteins is active and GSK3b phosphorylates b-catenin targeting it for proteasome degradation. Wnt activation implies the dissociation of the degradation complex and b-catenin translocation into the nucleus, where it activates the transcription of its target genes c-Myc and cyclin D1 which are involved in proliferation, migration, and survival (20,23,24,29,30). In prostate cancer cells, the knockdown of PKCd induced higher activation of b-catenin in comparison with siRNA control cells, as well as higher expression of its transcriptional targets.…”

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

“…In MM, aberrant activation of the canonical Wnt pathway drives proliferation and is associated with disease progression, dissemination, and drug resistance (5)(6)(7)(8)(9). Because MMs with hallmarks of active Wnt signaling do not harbor mutations that typically underlie constitutive Wnt pathway activation, this oncogenic Wnt pathway activity was proposed to involve autocrine and/or paracrine Wnt ligands (6,8,10).…”