Abstract
BackgroundProlactinoma 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.MethodsDownloaded 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.ResultsA 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.ConclusionOur study of identification and functional validation of TOPK suggests that this candidate can be a promising molecular target for prolactinoma treatment.
Highlights
Pituitary adenoma (PA) is one of the most common intracranial tumors, and its morbidity is about 16% as found by autopsy or Nuclear Magnetic Resonance Imaging [1]
By inhibiting T-LAK Cell-Originated Protein Kinase (TOPK) in vivo and in vitro, we explored the effect of HI-TOPK-032 on the proliferation, apoptosis, cell cycle distribution and migration of pituitary tumor cells, and investigated it’s effect on PRL secretion and tumor growth in prolactinoma model rats
Up-regulated genes were mainly enriched in biological processes, such as chromosome segregation, nuclear division and mitotic nuclear division, while down-regulated genes mainly participate in sensory system development and transmembrane receptor protein serine/threonine kinase signaling pathway
Summary
Pituitary adenoma (PA) is one of the most common intracranial tumors, and its morbidity is about 16% as found by autopsy or Nuclear Magnetic Resonance Imaging [1]. Prolactinoma is treated mainly by surgery and drug therapy to improve tumor occupying and hormone disturbance [10]. Dopamine agonists are the major first-line therapeutic drugs, including bromocriptine and cabergoline. There are such disadvantages as insufficient drug types and single treatment plans [11]. 10%-30% of patients become resistant to dopamine agonists [12]. For patients resistant to dopamine agonists and unsuitable for surgery, the treatment is still a clinical challenge. Prolactinoma is the most common type of pituitary tumors, and its resultant tumor occupying and hormone disturbance greatly damage the health of patients. 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
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