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.

2023-06-01·Journal of cellular and molecular medicine

KRAS^G12C mutation-induced TOPK overexpression contributes to tumour progression in non-small cell lung cancer.

Article

作者: Yao, Shuo ; Zhu, Junfei ; Chen, Xiuqiong ; Wang, Yali ; Lu, Hui ; Xiong, Hua ; Zhu, Feng ; Cai, Chang ; Zou, Yanmei ; Zheng, Kun ; Wang, Yihua

KRAS mutation is the most frequent type of genetic mutation in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma. However, KRAS mutation can affect many biological processes and the mechanisms underlying KRAS mutation-mediate carcinogenesis in NSCLC have not been fully understood. In this research, we found that KRAS^G12C mutation was associated with the upregulation of T-LAK cell-originated protein kinase (TOPK), which is a well-known serine/threonine MAPK-like protein kinase implicated in tumorigenesis. The overexpression of TOPK significantly promoted the malignant phenotype of A549 cells, and TOPK silencing impaired the malignant phenotype with KRAS^G12C mutation. Moreover, we demonstrated that TOPK level was regulated by MAPK/ERK signalling and the transcription factor Elk1. TOPK was also found to promote the activation of NF-κB signalling in A549 cells with KRAS^G12C mutation via facilitating the phosphorylation of TAK1. In the in vivo tumorigenesis model, the administration of TOPK inhibitor OTS514 enhanced the anticancer effect of 5-FU, and the combinatory use of OTS514 and KRAS^G12C inhibitor AMG510 showed synergistic anti-tumour effect. These results suggest that KRAS-TOPK axis contributes to the progression of NSCLC and targeting this axis could synergize with anticancer effect of the existing chemotherapeutics.

2023-04-11·ACS nano

Identifying TOPK and Hypoxia Hallmarks in Esophageal Tumors for Photodynamic/Chemo/Immunotherapy and Liver Metastasis Inhibition with Nanocarriers

Article

作者: Han, Junhong ; Zhao, Jinhua ; Mi, Peng ; Shi, Guidong ; Yuan, Yong ; Cui, Yongsheng ; Chen, Longqi ; Liu, Jing ; Wang, Yao ; Cheng, Xueqing ; Yang, Yushang

Although esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers, there are major bottlenecks in its therapeutic approaches, primarily the identification of clinically relevant targets and the lack of effective targeted therapeutics. Herein, we identified the hallmarks of ESCC, namely, high T-lymphokine-activated killer cell-originated protein kinase (TOPK) expression in human ESCC tumors and its correlation with poor patient prognosis and hypoxia in the tumor microenvironment. We developed hypoxia-sensitive nanoparticles encapsulating TOPK inhibitor OTS964 and photosensitizer chlorin e6 for the imaging-directed precision therapy of ESCC tumors. The sub-100 nm monodisperse nanoparticles efficiently delivered drugs into the human ESCC KYSE 150 cancer cells to kill the cells. The nanoparticles were selectively accumulated in the ESCC tumors after intravenous (i.v.) injection, thereby enabling the diagnosis and photoacoustic imaging-guided local laser irradiation of tumors. The combination of chemotherapy and photodynamic therapy effectively eradicated human ESCC KYSE 150 tumors and inhibited liver metastasis and recurrence by suppressing TOPK and inducing ESCC cell apoptosis. The nanoparticle-based therapies further stimulated high rates of natural killer cells in ESCC tumors, thereby exhibiting the potential of immunotherapy. This study identified important therapeutic targets of ESCC tumors and delineated an effective nanocarrier-based approach for tumor microenvironment and molecular targeted therapy.

100 项与 OTS-964 相关的药物交易

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