PBK/TOPK: A Therapeutic Target Worthy of Attention

Han, Ziping; Li, Lingzhi; Huang, Yuyou; Zhao, Haiping; Luo, Yumin

doi:10.3390/cells10020371

Cited by 41 publications

(43 citation statements)

References 73 publications

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“…Although previous studies [1,26,27] have reported higher expression of the PBK/TOPK mRNA and protein in tumor tissues than in adjacent noncancerous tissues from different tumors, this study was the first pan-cancer analysis of PBK/ TOPK and enabled us to observe the expression across all cancers. We only detected lower PBK/TOPK mRNA expression in LAML tissues than in normal tissues, which has not been reported in previous studies, although PBK/TOPK may mediate cell proliferation and viability in promyelocyte cell lines [28].…”

Section: Discussionmentioning

confidence: 90%

“…PDZ binding kinase (PBK) is a kinase that binds to the PDZ2 region of HDIG as first identified by an investigator screening a yeast two-hybrid system [1], and the gene was cloned from a HeLa cell cDNA library. T-LAK cell-derived protein kinase (TOPK) is a serine-threonine protein kinase identified from a cDNA library of activated lymphokineactivated killer T cells [2], and PBK was later identified as the same molecule as TOPK by a sequence analysis, hence receiving the name PBK/TOPK.…”

Section: Introductionmentioning

confidence: 99%

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PDZ Binding Kinase/T-LAK Cell-Derived Protein Kinase Plays an Oncogenic Role and Promotes Immune Escape in Human Tumors

Feng

Zhang

Ling

et al. 2021

Journal of Oncology

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Background. PDZ binding kinase (PBK)/T-LAK cell-derived protein kinase (TOPK) is an important mitotic kinase that promotes tumor progression in some cancers. However, the pan-cancer analysis of PBK/TOPK and its role in tumor immunity are limited. Methods. The oncogenic and immune roles of PBK in various cancers were explored using multiple databases, including Oncomine, Human Protein Atlas, ULCAN, Tumor Immune Estimation Resource 2.0, STRING, and Gene Expression Profiling Interactive Analysis 2, and data collected from The Cancer Genome Atlas and Genotype-Tissue Expression Project. Several bioinformatics tools and methods were used for quantitative analyses and panoramic descriptions, such as the DESeq2 and Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Results. PBK was expressed at higher levels in most solid tumors than in normal tissues in multiple databases. PBK was associated with an advanced tumor stage and grade and a poor prognosis in most cases. PBK was associated with tumor immune cell infiltration in most cases and was especially positively correlated with TAMs, Tregs, MDSCs, and T cell exhaustion in KIRC, LGG, and LIHC. PBK was closely related to TMB, MSI, and immune checkpoint genes in various cancers, and patients with higher expression of PBK in KIRC, LGG, and LIHC had higher TIDE scores and lower immune responses in the predicted results. PBK was closely related to cell cycle regulation and immune-related processes in LIHC and LGG according to GO and KEGG enrichment analyses. Conclusions. PBK may play an oncogenic role in most solid tumors and promotes immune escape, especially in KIRC, LGG, and LIHC. This study suggests the potential value of PBK inhibitors combined with immunotherapy.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

PDZ Binding Kinase/T-LAK Cell-Derived Protein Kinase Plays an Oncogenic Role and Promotes Immune Escape in Human Tumors

Feng

Zhang

Ling

et al. 2021

Journal of Oncology

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“…Currently, the functions of TOPK and its inhibitors have been reviewed in individual studies [ 128 ]; however, no comprehensive or intuitive works have been published, and, thus, a strength of the current paper is that it is more profound and broader than previous reports. In addition, drugs targeting TOPK are not used as frequently as AKT or AURKA drugs in clinical settings [ 129 , 130 ]; however, TOPK is identified here as a novel prognostic predictive factor and is involved in several signaling pathways, such as the MAPK and AKT pathways.…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

PBK/TOPK: An Effective Drug Target with Diverse Therapeutic Potential

Huang

Lee

Liu

et al. 2021

Cancers

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T-lymphokine-activated killer cell-originated protein kinase (TOPK, also known as PDZ-binding kinase or PBK) plays a crucial role in cell cycle regulation and mitotic progression. Abnormal overexpression or activation of TOPK has been observed in many cancers, including colorectal cancer, triple-negative breast cancer, and melanoma, and it is associated with increased development, dissemination, and poor clinical outcomes and prognosis in cancer. Moreover, TOPK phosphorylates p38, JNK, ERK, and AKT, which are involved in many cellular functions, and participates in the activation of multiple signaling pathways related to MAPK, PI3K/PTEN/AKT, and NOTCH1; thus, the direct or indirect interactions of TOPK make it a highly attractive yet elusive target for cancer therapy. Small molecule inhibitors targeting TOPK have shown great therapeutic potential in the treatment of cancer both in vitro and in vivo, even in combination with chemotherapy or radiotherapy. Therefore, targeting TOPK could be an important approach for cancer prevention and therapy. Thus, the purpose of the present review was to consider and analyze the role of TOPK as a drug target in cancer therapy and describe the recent findings related to its role in tumor development. Moreover, this review provides an overview of the current progress in the discovery and development of TOPK inhibitors, considering future clinical applications.

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“…T-lymphokine-activated killer-cell-originated protein kinase (TOPK), also known as PDZ-binding kinase (PBK), is a novel mitotic serine/threonine protein kinase, which was con rmed to be associated with the development, progression, and metastasis of malignancies and to be a potential therapeutic target in cancer therapy [37]. Studies have shown that PBK expression is increased in various cancers compared with in normal tissues [38].In this study, we explored the expression of PBK in pan-cancers using oncomine and TIMER databases.…”

Section: Discussionmentioning

confidence: 99%

High Expression of PDZ-binding Kinase Is Correlated With Poor Prognosis and Immune Infiltrates in Hepatocellular Cacinoma

Xie

et al. 2021

Preprint

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BackgroundPDZ-binding kinase (PBK) encodes a serine/threonine protein kinase related to the dual specific mitogen-activated protein kinase kinase (MAPKK) family. There is evidence that overexpression of this gene is associated with tumorigenesis. However, the role of PBK in hepatocellular carcinoma (HCC) remain unclear. Therefore, we evaluated the prognostic role of PBK and its correlation with immune infiltrates in Hepatocellular Carcinoma.MethodsThe expression of PBK in pan-cancers was studied by Onconmine and TIMER. The expression of PBK in HCC patients and its relationship with clinicopathological characteristics were analyzed using The Gene Expression Profiling Interactive Analysis (GEPIA), The human protein atlas database (HPA), The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Receiver operating characteristic (ROC) curve was used to determine the diagnostic value of PBK in HCC patients. The relationship between PBK and prognosis of HCC was performed by GEPIA and Kaplan Meier plotter web tool. The correlations between the clinical characteristics and overall survival were analyzed by Univariate Cox regression and Multivariate Cox hazards regression to identify possible prognostic factors for HCC patients. LinkedOmics was applied to investigate co-expression associated with PBK and to analyze Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The network map of PBK and related genes is constructed by GeneMANIA. Finally, TIMER and TISIDB were used to analyze the correlations between PBK and tumor-infiltrating immune cells.ResultsPBK was highly expressed in many types of tumors, including hepatocellular carcinoma, and was significantly related to tumor stage (P=0.0089), age (P=0.0131) and race (P=0.0024) of HCC patients. The receiver operating characteristic (ROC) curve analysis from 4 GEO databases showed that PBK is a predictive marker for HCC. Moreover, high expression of PBK correlated with poor prognosis. Multivariate Cox hazards regression showed that high expression of PBK may be an independent risk factor for overall survival in HCC patients (HR = 1.566, 95% CI=1.062-2.311, P= 0.024). The Protein–protein interaction network showed that PBK significantly interacted with LRRC47, ARAF, LGALS9B, TTK, MELK and other essential genes. Furthermore, enrichment analysis showed that PBK and co-expressed genes participated in many biological processes, cell composition, molecular functions and pathways in HCC. Finally, the immune infiltration analysis by TIMER and TISIDB indicated that PBK expression tightly correlated with the infiltration of tumor-infiltrating lymphocytes (TILs), chemokines, and receptors.ConclusionsHigh expression of PBK is significantly correlated with poor survival and immune infiltrates in hepatocellular carcinoma. Our study suggests that PBK can be used as a biomarker of poor prognosis and potential immune therapy target in hepatocellular carcinoma.

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PBK/TOPK: A Therapeutic Target Worthy of Attention

Cited by 41 publications

References 73 publications

PDZ Binding Kinase/T-LAK Cell-Derived Protein Kinase Plays an Oncogenic Role and Promotes Immune Escape in Human Tumors

PDZ Binding Kinase/T-LAK Cell-Derived Protein Kinase Plays an Oncogenic Role and Promotes Immune Escape in Human Tumors

PBK/TOPK: An Effective Drug Target with Diverse Therapeutic Potential

High Expression of PDZ-binding Kinase Is Correlated With Poor Prognosis and Immune Infiltrates in Hepatocellular Cacinoma

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