Novel Interleukin-6 Inducible Gene PDZ-Binding Kinase Promotes Tumor Growth of Multiple Myeloma Cells

Ota, Akinobu; Hanamura, Ichiro; Karnan, Sivasundaram; Inaguma, Shingo; Takei, Norio; Lam, Vu Quang; Mizuno, Shohei; Kanasugi, Jo; Wahiduzzaman, Md; Rahman, Lutfur; Hyodo, Toshinori; Konishi, Hiroyuki; Tsuzuki, Shinobu; Ikeda, Hiroshi; Takami, Akiyoshi; Hosokawa, Yoshitaka

doi:10.1089/jir.2020.0111

Cited by 10 publications

(14 citation statements)

References 55 publications

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“…In contrast to reports in malignant tumors such as multiple myeloma in which PBK enhances the malignant potential of tumor cells and is associated with unfavorable clinical outcome ( Brown-Clay et al, 2015 ; Kwon et al, 2016 ; Ohashi et al, 2016 ; Ohashi et al, 2017 ; Yang et al, 2017 ; Ota et al, 2020 ), our study revealed favorable survival of CRC patients with PBK-high tumors ( Nagano-Matsuo et al, 2021 ). PBK showed a significant positive association with Ki-67, a widely used cellular proliferation marker, along with a significant inverse association to pT stage in CRC ( Nagano-Matsuo et al, 2021 ).…”

Section: Discussioncontrasting

confidence: 99%

“…Several PBK-targeting compounds such as HI-TOPK-032, SKLB-C05 and Ginsenoside Rh2 have been reported to suppress tumor growth and/or metastasis of CRC ( Gao et al, 2019 ; Yang et al, 2016 ; Kim et al, 2012 ). Our group successfully inhibited the growth of multiple myeloma and CRC cells using OTS514, a specific PBK inhibitor ( Figures 2C,D ) ( Ota et al, 2020 ; Nagano-Matsuo et al, 2021 ). OTS514 not only suppressed the cellular proliferation of CRC cells but it also induced apoptosis with down-regulation of PHH3.…”

Section: Discussionmentioning

confidence: 98%

“…Previous studies revealed that PBK is involved in cytokinesis and spermatogenesis ( Gaudet et al, 2000 ; Matsumoto et al, 2004 ; Fujibuchi et al, 2005 ; Abe et al, 2007 ; Park et al, 2010 ). PBK has also been reported to enhance the malignant potential of cells, such as by promoting cellular proliferation of tumor cells, and its expression in malignant tumors such as multiple myeloma is associated with patient survival ( Brown-Clay et al, 2015 ; Kwon et al, 2016 ; Ohashi et al, 2016 ; Ohashi et al, 2017 ; Yang et al, 2017 ; Ota et al, 2020 ). Several reports have also provided evidence for the anticancer effects of PBK inhibitors on cancer cells ( Yang et al, 2016 ; Herbert et al, 2018 ; Gao et al, 2019 ; Zhao et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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PBK Enhances Cellular Proliferation With Histone H3 Phosphorylation and Suppresses Migration and Invasion With CDH1 Stabilization in Colorectal Cancer

et al. 2022

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Colorectal cancer (CRC) is one of the most frequent gastrointestinal malignancies with high morbidity and mortality rates. Several biological markers for the prognostication of patient outcome of CRCs are available. Recently, our group identified two favorable factors for the survival of CRC patients: PDZ-binding kinase (PBK) and phospho-histone H3 (PHH3). Both showed a significant inverse association to pT stage. The aim of this study was to uncover the mechanism through which these cellular proliferation–associated protein expressions lead to favorable clinical outcome in CRC patients. We first confirmed co-expression of PBK and PHH3 in CRC cells. Further investigation showed that aberrantly expressed PBK up-regulated the cellular proliferation of CRC cells with accumulation of PHH3. The PBK inhibitor OTS514 suppressed cellular proliferation of CRC cells through down-regulation of PHH3 and induction of apoptosis. In vitro studies revealed that PBK suppressed the migration and invasion of CRC cells with suppression of Wnt/β-catenin signaling and CDH1 stabilization. Exogeneous PBK up-regulated the phosphorylated CDH1 at S840, S846, and S847 residues in cultured cells. Recombinant PBK directly phosphorylated HH3; however, it failed to phosphorylate CDH1 directly in vitro. The present study demonstrated the association of two markers PBK and PHH3 in CRC. We further identified one of the potential mechanisms by which higher expression of these cellular proliferation–associated proteins leads to the better survival of CRC patients, which likely involves PBK-mediated suppression of the migration and invasion of CRC cells. Our findings suggest that PBK-targeting therapeutics may be useful for the treatment of CRC patients with PBK-expressing tumors.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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PBK Enhances Cellular Proliferation With Histone H3 Phosphorylation and Suppresses Migration and Invasion With CDH1 Stabilization in Colorectal Cancer

et al. 2022

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“…PDZK1 is overexpressed in MM cell lines and drives resistance to chemotherapy in vitro 50 . Although this has been largely underexplored, a recent study showed that PDZ binding kinase is induced by IL-6 and promotes growth through STAT3 pathway 51 , yet another example of a protein at the 1q21 locus that is involved in the IL6-STAT3 continuum. PSMD4 and ILF2 have been implicated in resistance to specific treatments and are summarized later in the review.…”

Section: Potential Genetic Drivers On Chromosome 1qmentioning

confidence: 99%

Chromosome 1q21 abnormalities in multiple myeloma

2021

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Gain of chromosome 1q (+1q) is one of the most common recurrent cytogenetic abnormalities in multiple myeloma (MM), occurring in approximately 40% of newly diagnosed cases. Although it is often considered a poor prognostic marker in MM, +1q has not been uniformly adopted as a high-risk cytogenetic abnormality in guidelines. Controversy exists regarding the importance of copy number, as well as whether +1q is itself a driver of poor outcomes or merely a common passenger genetic abnormality in biologically unstable disease. Although the identification of a clear pathogenic mechanism from +1q remains elusive, many genes at the 1q21 locus have been proposed to cause early progression and resistance to anti-myeloma therapy. The plethora of potential drivers suggests that +1q is not only a causative factor or poor outcomes in MM but may be targetable and/or predictive of response to novel therapies. This review will summarize our current understanding of the pathogenesis of +1q in plasma cell neoplasms, the impact of 1q copy number, identify potential genetic drivers of poor outcomes within this subset, and attempt to clarify its clinical significance and implications for the management of patients with multiple myeloma.

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“…9 Furthermore, it has been reported that inhibiting TOPK by specific inhibitors, OTS514 and OTS964, effectively inhibits the proliferation of many tumour cells. [30][31][32][33] Clinical studies reported that the expression of TOPK was strongly associated with poor prognosis of cancer patients. [34][35][36] As a potential tumour marker, TOPK has attracted extensive attention from basic and clinical researchers.…”

Section: Discussionmentioning

confidence: 99%

Topical application of TOPK inhibitor OTS514 suppresses psoriatic progression by inducing keratinocytes cell cycle arrest and apoptosis

Fan-dian

Lü

et al. 2023

Experimental Dermatology

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T‐LAK cell‐oriented protein kinase (TOPK) potently promotes malignant proliferation of tumour cells and is considered as a maker of tumour progression. Psoriasis is a common inflammatory skin disease characterized by abnormal proliferation of keratinocytes. However, the role of TOPK in psoriasis has not been well elucidated. This study aims to investigate the expression and role of TOPK in psoriasis, and the role of TOPK inhibitor in psoriasis attenuation. Gene Expression Omnibus datasets derived from psoriasis patients and psoriatic model mice were screened for analysis. Skin specimens from psoriasis patients were collected for TOPK immunohistochemical staining to investigate the expression and localization of TOPK. Next, psoriatic mice model was established to further confirm TOPK expression pattern. Then, TOPK inhibitor was applied to investigate the role of TOPK in psoriasis progression. Finally, cell proliferation assay, apoptosis assay and cell cycle analysis were performed to investigate the potential mechanism involved. Our study showed that TOPK was upregulated in the lesions of both psoriasis patients and psoriatic model mice, and TOPK levels were positively associated with psoriasis progression. TOPK was upregulated in psoriatic lesions and expressed predominantly by epidermal keratinocytes. In addition, TOPK levels in epidermal keratinocytes were positively correlated with epidermal hyperplasia. Furthermore, topical application of TOPK inhibitor OTS514 obviously alleviated disease severity and epidermal hyperplasia. Mechanismly, inhibiting TOPK induces G2/M phase arrest and apoptosis of keratinocytes, thereby attenuating epidermal hyperplasia and disease progression. Collectively, this study identifies that upregulation of TOPK in keratinocytes promotes psoriatic progression, and inhibiting TOPK attenuates epidermal hyperplasia and psoriatic progression.

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Novel Interleukin-6 Inducible Gene PDZ-Binding Kinase Promotes Tumor Growth of Multiple Myeloma Cells

Cited by 10 publications

References 55 publications

PBK Enhances Cellular Proliferation With Histone H3 Phosphorylation and Suppresses Migration and Invasion With CDH1 Stabilization in Colorectal Cancer

PBK Enhances Cellular Proliferation With Histone H3 Phosphorylation and Suppresses Migration and Invasion With CDH1 Stabilization in Colorectal Cancer

Chromosome 1q21 abnormalities in multiple myeloma

Topical application of TOPK inhibitor OTS514 suppresses psoriatic progression by inducing keratinocytes cell cycle arrest and apoptosis

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