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PBK/TOPK Inhibitor Suppresses the Progression of Prolactinomas
Kejing Zhu1,2,3,4, Xueting Cheng5, Shuman Wang4
1Department of Pharmacy, Tongren Hospital Affiliated to Wuhan University, The Third Hospital of Wuhan, Wuhan, China.
Background:
Prolactinoma is the most common type of pituitary tumors, and its resultant tumor occupying and hormone disturbance greatly damage the health of patients. In this study, we investigated a protein kinase-PDZ Binding Kinase (PBK)/T-LAK Cell-Originated Protein Kinase (TOPK) as a candidate protein regulating prolactin (PRL) secretion and tumor growth of prolactinomas.
Methods:
Downloaded prolactinoma transcriptome dataset from Gene Expression Omnibus (GEO) database, and screened differentially expressed genes (DEGs) between normal pituitary tissues and prolactinoma tissues. Then, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed, a protein-protein interaction (PPI) network was constructed and the hub genes were identified. After a literature search, TOPK was presumed as an candidate target regulating the prolactinoma. We found a specific inhibitor of TOPK to investigate its effects on the proliferation, migration, apoptosis and PRL secretion of pituitary tumor cells. Finally, the regulation of TOPK inhibitor on its downstream target-p38 Mitogen Activated Protein Kinase (p38 MAPK) was detected to explore the potential mechanism.
Results:
A total of 361 DEGs were identified, and 20 hub genes were screened out. TOPK inhibitor HI-TOPK-032 could suppress the proliferation & migration and induce apoptosis of pituitary tumor cells in vitro, and reduce PRL secretion and tumor growth in vivo. HI-TOPK-032 also inhibited the phosphorylation level of the downstream target p38 MAPK, suggesting that TOPK inhibitors regulate the development of prolactinoma by mediating p38 MAPK.
Conclusion:
Our study of identification and functional validation of TOPK suggests that this candidate can be a promising molecular target for prolactinoma treatment.
Insights
T-LAK Cell-Originated Protein Kinase (TOPK) is a promising target for prolactinoma treatment. Inhibiting TOPK suppressed pituitary tumor growth and prolactin secretion by affecting p38 MAPK signaling.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Prolactinoma, the most common pituitary tumor, causes significant health issues due to hormone imbalance and tumor growth.
- Investigating T-LAK Cell-Originated Protein Kinase (TOPK) as a key regulator of prolactin secretion and prolactinoma progression.
Purpose of the Study:
- To identify novel molecular targets for prolactinoma treatment.
- To evaluate the therapeutic potential of targeting TOPK in prolactinoma.
Main Methods:
- Transcriptome analysis of prolactinoma tissues to identify differentially expressed genes (DEGs).
- Bioinformatic analyses including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) network construction to identify hub genes.
- In vitro and in vivo studies using a specific TOPK inhibitor (HI-TOPK-032) to assess its effects on pituitary tumor cells and prolactinoma growth.
- Analysis of downstream signaling pathways, specifically p38 Mitogen Activated Protein Kinase (p38 MAPK).
Main Results:
- 361 DEGs and 20 hub genes were identified, with TOPK emerging as a key candidate.
- TOPK inhibition by HI-TOPK-032 suppressed pituitary tumor cell proliferation and migration, induced apoptosis, and reduced prolactin secretion in vitro.
- HI-TOPK-032 administration reduced prolactinoma tumor growth in vivo and inhibited p38 MAPK phosphorylation.
Conclusions:
- TOPK plays a significant role in prolactinoma development.
- Targeting TOPK with inhibitors like HI-TOPK-032 shows therapeutic promise for prolactinoma.
- The mechanism involves the regulation of p38 MAPK signaling by TOPK inhibitors.
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