NEK2 induces osteoclast differentiation and bone destruction via heparanase in multiple myeloma

Hao, Mu; Franqui-Machin, Reinaldo; Xu, Hui; Shaughnessy, John D.; Barlogie, Bart; Roodman, David; Quelle, Dawn E.; Janz, Siegfried; Tomasson, Michael H.; Sanderson, RD; Qiu, Luqui; Frech, Ivana; Tricot, Guido; Zhan, Fenghuang

doi:10.1038/leu.2017.115

Cited by 31 publications

(37 citation statements)

References 14 publications

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“…Additionally, the interaction between USP7-NEK2, leading to the deubiquitination and stabilization of NEK2, was confirmed [80]. Moreover, high expression of NEK2 was observed in MM cells with an increase in focal bony lesions [81].…”

Section: Nek2mentioning

confidence: 74%

Checking NEKs: Overcoming a Bottleneck in Human Diseases

et al. 2020

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In previous years, several kinases, such as phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular-signal-regulated kinase (ERK), have been linked to important human diseases, although some kinase families remain neglected in terms of research, hiding their relevance to therapeutic approaches. Here, a review regarding the NEK family is presented, shedding light on important information related to NEKs and human diseases. NEKs are a large group of homologous kinases with related functions and structures that participate in several cellular processes such as the cell cycle, cell division, cilia formation, and the DNA damage response. The review of the literature points to the pivotal participation of NEKs in important human diseases, like different types of cancer, diabetes, ciliopathies and central nervous system related and inflammatory-related diseases. The different known regulatory molecular mechanisms specific to each NEK are also presented, relating to their involvement in different diseases. In addition, important information about NEKs remains to be elucidated and is highlighted in this review, showing the need for other studies and research regarding this kinase family. Therefore, the NEK family represents an important group of kinases with potential applications in the therapy of human diseases.

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Section: Nek2mentioning

confidence: 74%

Checking NEKs: Overcoming a Bottleneck in Human Diseases

et al. 2020

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“…transcription factor, we further evaluated the expression of a direct target in isogenic myeloma cell lines. Our group recently reported that NEK2 activates heparanase (HPSE), a secreted endoglycosidase responsible for bone destruction in myeloma patients through increased stimulation of osteoclast differentiation and that it is also a direct NF-κB target, as listed in Supplemental Table 2 (40). We found that inhibition of HPSE expression with smallmolecule drugs inhibited osteoclast differentiation and osteolysis induced by NEK2 in vivo.…”

Section: Than Control Cells (Supplementalmentioning

confidence: 80%

Destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma

Franqui-Machin¹,

Hao

Bai

et al. 2018

Journal of Clinical Investigation

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Drug resistance remains the key problem in cancer treatment. It is now accepted that each myeloma patient harbors multiple subclones and subclone dominance may change over time. The coexistence of multiple subclones with high or low chromosomal instability (CIN) signature causes heterogeneity and drug resistance with consequent disease relapse. In this study, using a tandem affinity purification-mass spectrometry (TAP-MS) technique, we found that NEK2, a CIN gene, was bound to the deubiquitinase USP7. Binding to USP7 prevented NEK2 ubiquitination resulting in NEK2 stabilization. Increased NEK2 kinase levels activated the canonical NF-κB signaling pathway through the PP1α/AKT axis. Newly diagnosed myeloma patients with activated NF-κB signaling through increased NEK2 activity had poorer event-free and overall survivals based on multiple independent clinical cohorts. We also found that NEK2 activated heparanase, a secreted enzyme, responsible for bone destruction in an NF-κB-dependent manner. Intriguingly, both NEK2 and USP7 inhibitors showed great efficacy in inhibiting myeloma cell growth and overcoming NEK2-induced and -acquired drug resistance in xenograft myeloma mouse models.

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“…This NA-ROH (Mw 16 kDa) demonstrated a remarkable antitumor, antiangiogenic, immunomodulatory and antimetastatic activity in several preclinical models of both hematological (e.g., multiple myeloma, lymphoma) and solid tumors (e.g., sarcomas, pancreatic and breast carcinoma). It was safely administered in mice in prolonged treatment schedules both alone and in combination with other antitumor agents [151][152][153][154][155][156][157][158][159]. An excellent safety profile was also emerged by recent results of Phase I clinical trial in advanced relapsed/refractory multiple myeloma [160] (Noseda and Barbieri, Chap.…”

Section: Roneparstat (G4000 100 Na-roh Sst0001)mentioning

confidence: 99%