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Although treatment of chronic myeloid leukemia (CML) has improved with the development of tyrosine kinase inhibitors (TKIs), patients develop fatal blast crisis (BC) whilst receiving TKI treatment. Alternative treatments for cases resistant to TKIs are required. A serine/threonine protein kinase, T-lymphokine-activated killer cell-originated protein kinase (TOPK), is highly expressed in various malignant tumors. Binding of peptides to human leukocyte antigen was assessed via mass spectrometry in K562 CML cells. TOPK expression was assessed in various CML cell lines and in clinical samples obtained from patients with CML using reverse transcription-quantitative polymerase chain reaction and western blot assays. It was observed that TOPK was expressed abundantly in BCR/ABL-positive cell lines and at significantly higher levels in CML clinical samples compared with healthy donor samples. Overexpression of BCR/ABL or the presence of its inhibitor imatinib upregulated and downregulated TOPK expression, respectively, indicating that TOPK may be a target of BCR/ABL. TOPK inhibitor OTS514 suppressed proliferation of BCR/ABL-positive cell lines and colony formation of CD34-positive cells from patients with CML compared with lymphoma patients without bone marrow involvement. Furthermore, phosphorylation of TOPK was increased by protein phosphatase 2A (PP2A) inhibitor okadaic acid and was decreased in the presence of PP2A activator FTY720 compared with untreated samples. As constitutive BCR/ABL activity and inhibition of PP2A are key mechanisms of CML development, TOPK may be a crucial signaling molecule for this disease. Inhibition of TOPK may control disease status of CML, even in cases resistant to TKIs.

The senescence of bone marrow mesenchymal stem cells (BMSCs) contributes to the development of degenerative skeletal conditions. To date, the molecular mechanism resulting in BMSC senescence has not been fully understood. In this study, we identified a small non‐coding RNA, miR‐203‐3p, the expression of which was elevated in BMSCs from aged mice. On the other hand, overexpression of miR‐203‐3p in BMSCs from young mice reduced cell growth and enhanced their senescence. Mechanistically, PDZ‐linked kinase (PBK) is predicted to be the target of miR‐203‐3p. The binding of miR‐203‐3p to Pbk mRNA could decrease its expression, which in turn inhibited the ubiquitination‐mediated degradation of p53. Furthermore, the intravitreal injection of miR‐203‐3p‐inhibitor into the bone marrow cavity of aged mice attenuated BMSC senescence and osteoporosis in aged mice. Collectively, these findings suggest that targeting miR‐203‐3p to delay BMSC senescence could be a potential therapeutic strategy to alleviate age‐related osteoporosis. This study indicates that inhibiting miR‐203‐3p (partly via the PBK/p53 signaling pathway) improves cell growth dynamics and slows the process of cellular senescence, rejuvenating senescent BMSCs. Furthermore, it presents a new potential target for delaying age‐related osteoporosis.

Adult T-cell leukemia/lymphoma (ATLL) is a disorder involving human T-cell leukemia virus type 1 (HTLV-1)-infected T-cells characterized by increased clonal neoplastic proliferation. PDZ-binding kinase (PBK) [also known as T-lymphokine-activated killer cell-originated protein kinase (TOPK)] is a serine/threonine kinase expressed in proliferative cells and is phosphorylated during mitosis. In this study, the expression and phosphorylation of PBK/TOPK were examined by western blot analysis and RT-PCR. We found that PBK/TOPK was upregulated and phosphory-lated in HTLV-1-transformed T-cell lines and ATLL-derived T-cell lines. Notably, CDK1/cyclin B1, which phosphorylates PBK/TOPK, was overexpressed in these cells. HTLV-1 infection upregulated PBK/TOPK expression in peripheral blood mononuclear cells (PBMCs) in co-culture assays. The potent PBK/TOPK inhibitors, HI-TOPK-032, and fucoidan from brown algae, decreased the proliferation and viability of these cell lines in a dose-dependent manner. By contrast, the effect of HI-TOPK-032 on PBMCs was less pronounced. Treatment with HI-TOPK-032 resulted in G1 cell cycle arrest, and decreased CDK6 expression and pRb phosphorylation, which are critical determinants of progression through the G1 phase. In addition, HI-TOPK-032 induced apoptosis, as evidenced by morphological changes, the cleavage of poly(ADP-ribose) polymerase with the activation of caspase−3, −8 and −9, and an increase in the sub-G1 cell population and APO2.7-positive cells. Moreover, HI-TOPK-032 inhibited the expression of cellular inhibitor of apoptosis 2 (c-IAP2), X-linked inhibitor of apoptosis protein (XIAP), survivin and myeloid cell leukemia-1 (Mcl-1), and induced the expression of Bak and interferon-induced protein with tetratricopeptide repeats (IFIT)1, 2 and 3. It is noteworthy that the use of this inhibitor led to the inhibition of the phosphorylation of IκB kinase (IKK)α, IKKβ, IκBα, phosphatase and tensin homolog (PTEN) and Akt, and to the decreased protein expression of JunB and JunD, suggesting that PBK/TOPK affects the nuclear factor-κB, Akt and activator protein-1 signaling pathways. In vivo, the administration of HI-TOPK-032 suppressed tumor growth in an ATLL xenograft model. Thus, on the whole, this study on the identification and functional analysis of PBK/TOPK suggests that this kinase is a promising molecular target for ATLL treatment.

Nasopharyngeal carcinoma (NPC) is a common cancer found in the nasopharynx, which plagues countless NPC patients. MicroRNA‐372 (miR‐372) has been reported to be involved in various tumors. Here, we explored the important role of miR‐372 in radiosensitivity, invasion, and metastasis of NPC. Microarray analysis was conducted to search the NPC‐related differentially expressed genes (DEGs) and predict the miRs regulating PBK, which suggested that miR‐372 could influence the development of NPC via PBK and the p53 signaling pathway. Importantly, miR‐372 was observed to target PBK, thus down‐regulating its expression. Then, NPC 5‐8F and C666‐1 cells were selected, and treated with ionization radiation and alteration of miR‐372 and PBK expression to explore the functional role of miR‐372 in NPC. The expression of miR‐372, PBK, Bcl‐2, p53, and Bax as well as the extent of Akt phosphorylation were measured. In addition, cell colony formation, cell cycle, proliferation, apoptosis, migration, and invasion were detected. At last, tumor growth and the effect of miR‐372 on radiosensitivity of NPC were evaluated. Besides, over‐expressed miR‐372 down‐regulated Bcl‐2 and PBK expression and the extent of Akt phosphorylation while up‐regulated the expression of p53 and Bax. Additionally, miR‐372 over‐expression and radiotherapy inhibited cell clone formation, proliferation, tumor growth, migration, invasion, and cell cycle entry, but promoted cell apoptosis. However, the restoration of PBK in NPC cells expressing miR‐372 reversed the anti‐tumor effect of miR‐372 and activation of the p53 signaling pathway. In conclusion, the study shows that up‐regulated miR‐372 promotes radiosensitivity by activating the p53 signaling pathway via inhibition of PBK. In conclusion, the study shows that up‐regulated miR‐372 promotes radiosensitivity by activating the p53 signaling pathway via inhibition of PBK.

Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor whose median survival is less than 15 months. The current treatment regimen comprising surgical resectioning, chemotherapy with Temozolomide (TMZ), and adjuvant radiotherapy does not achieve total patient cure. Stem cells’ presence and GBM tumor heterogeneity increase their resistance to TMZ, hence the poor overall survival of patients. A dysregulated cell cycle in glioblastoma enhances the rapid progression of GBM by evading senescence or apoptosis through an over-expression of cyclin-dependent kinases and other protein kinases that are the cell cycle’s main regulatory proteins. Herein, we identified and validated the biomarker and predictive properties of a chemoradio-resistant oncogenic signature in GBM comprising CDK1, PBK, and CHEK1 through our comprehensive in silico analysis. We found that CDK1/PBK/CHEK1 overexpression drives the cell cycle, subsequently promoting GBM tumor progression. In addition, our Kaplan–Meier survival estimates validated the poor patient survival associated with an overexpression of these genes in GBM. We used in silico molecular docking to analyze and validate our objective to repurpose Dapagliflozin against CDK1/PBK/CHEK1. Our results showed that Dapagliflozin forms putative conventional hydrogen bonds with CDK1, PBK, and CHEK1 and arrests the cell cycle with the lowest energies as Abemaciclib.

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide with high morbidity and mortality rates. The discovery of small molecule anticancer reagents has significantly affected cancer therapy. However, the anticancer effects of these therapies are not sufficient to completely cure CRC. PDZ-binding kinase (PBK) was initially identified as a mitotic kinase for mitogen-activated protein kinase and is involved in cytokinesis and spermatogenesis. Aberrant expression of PBK has been reported to be closely associated with malignant phenotypes of many cancers and/or patient survival. However, the expression of PBK and its association to patient survival in CRC have not been fully elucidated. In the present study, 269 primary CRCs were evaluated immunohistochemically for PBK expression to assess its ability as a prognostic factor. CRC tumor cells variably expressed PBK (range, 0–100%; median, 32%) in the nucleus and cytoplasm. Univariate analyses identified a significant inverse correlation between PBK expression and pT stage (P<0.0001). Furthermore, patients carrying CRC with higher PBK expression showed significantly favorable survival (P=0.0094). Multivariate Cox proportional hazards regression analysis revealed high PBK expression (HR, 0.52; P=0.015) as one of the potential favorable factors for CRC patients. PBK expression showed significant correlation to Ki-67 labeling indices (ρ=0.488, P<0.0001). In vitro, the PBK inhibitor OTS514 suppressed cellular proliferation of CRC cells with PBK expression through downregulation of P-ERK and induction of apoptosis. These results suggest that PBK-targeting therapeutics may be useful for the treatment of PBK-expressing CRC patients.

Highlights ABCB1 overexpression significantly desensitized both drug-selected and gene-transfected cells, which overexpress ABCB1, to OTS964 and that this drug resistance can be antagonized by verapamil, a known ABCB1 inhibitor. Consistently, a similar trend was observed in tumor-bearing mice. OTS964 stimulated ATPase activity of ABCB1 and upregulated expression levels of ABCB1, resulting in induced resistance to other ABCB1 substrate-drugs, such as paclitaxel. OTS964 received a comparable affinity score and can dock into the substrate-binding site of human ABCB1 protein.

Medulloblastoma (MB) is the most frequent malignant brain tumor in pediatrics. Since the current standard of care for MB consisting of surgery, cranio-spinal irradiation and chemotherapy often leads to a high morbidity rate, a number of patients suffer from long-term sequelae following treatment. Targeted therapies hold the promise of being more effective and less toxic. Therefore, the present study aimed to identify hub genes with an upregulated expression in MB and to search for potential therapeutic targets from these genes. For this purpose, gene expression profile datasets were obtained from the Gene Expression Omnibus database and processed using R 3.6.0 software to screen differentially expressed genes (DEGs) between MB samples and normal brain tissues. A total of 282 upregulated and 436 downregulated DEGs were identified. Functional enrichment analysis revealed that the upregulated DEGs were predominantly enriched in the cell cycle, DNA replication and cell division. The top 10 hub genes were identified from the protein-protein interaction network of upregulated genes, and one identified hub gene [PDZ binding kinase (PBK)] was selected for further investigation due to its possible role in the pathogenesis of MB. The aberrant expression of PBK in MB was verified in additional independent gene expression datasets. Survival analysis demonstrated that a higher expression level of PBK was significantly associated with poorer clinical outcomes in non-Wingless MBs. Furthermore, targeting PBK with its inhibitor, HI-TOPK-032, impaired the proliferation and induced the apoptosis of two MB cell lines, with the diminished phosphorylation of downstream effectors of PBK, including ERK1/2 and Akt, and the activation of caspase-3. Hence, these results suggest that PBK may be a potential prognostic biomarker and a novel candidate of targeted therapy for MB.

PBK/TOPK (PDZ-binding kinase, T-LAK-cell-originated protein kinase) is a serine-threonine kinase that is overexpressed in a variety of tumor cells but its role in oncogenesis remains unclear. Here we show, by co-immunoprecipitation experiments and yeast two-hybrid analysis, that PBK/TOPK physically interacts with the tumor suppressor p53 through its DNA-binding (DBD) domain in HCT116 colorectal carcinoma cells that express wild-type p53. PBK also binds to p53 mutants carrying five common point mutations in the DBD domain. The PBK–p53 interaction appears to downmodulate p53 transactivation function as indicated by PBK/TOPK knockdown experiments, which show upregulated expression of the key p53 target gene and cyclin-dependent kinase inhibitor p21 in HCT116 cells, particularly after genotoxic damage from doxorubicin. Furthermore, stable PBK/TOPK knockdown cell lines (derived from HCT116 and MCF-7 cells) showed increased apoptosis, G 2 /M arrest and slower growth as compared to stable empty vector-transfected control cell lines. Gene microarray studies identified additional p53 target genes involved in apoptosis or cell cycling, which were differentially regulated by PBK knockdown. Together, these data suggest that increased levels of PBK/TOPK may contribute to tumor cell development and progression through suppression of p53 function and consequent reductions in the cell-cycle regulatory proteins such as p21. PBK/TOPK may therefore be a valid target for antineoplastic kinase inhibitors to sensitize tumor cells to chemotherapy-induced apoptosis and growth suppression.

To investigate the impact of PDZ-binding kinase (PBK) on the clinical outcome of patients with oral squamous cell carcinoma (OSCC) who received radiotherapy. PBK immunoreactivity of cancer specimens obtained from 179 patients with primary OSCC was analyzed by immunohistochemistry. High PBK expression in tumor cells tended to be associated with advanced N-stage. The 5-year survival rate was greater for patients with high total PBK expression than in those with low PBK expression. After adjustment, high PBK remained associated with a favorable outcome. In subgroups according to tumor stage, the prognostic role was significant in patients with stage III/IV rather than those with stage I/II disease. We suggest that PBK expression should be used as an independent prognostic marker for patients with OSCC treated with radiotherapy, especially for those with advanced-stage disease.