细胞周期
激酶
葡萄孢霉素
蛋白激酶A
生物
细胞凋亡
癌症研究
细胞生物学
癌症
癌细胞
癌基因
分子生物学
生物化学
遗传学
作者
Gauri Misra,Jyotika Rajawat,Rajesh Pal,Jeremy C. Smith,Amit Kumar
出处
期刊:Life Sciences
[Elsevier]
日期:2023-11-05
卷期号:334: 122250-122250
被引量:1
标识
DOI:10.1016/j.lfs.2023.122250
摘要
Microtubule-associated serine/threonine kinase-like (MASTL) (or Greatwall kinase (GWL)) is an important cell cycle regulating kinase that regulates the G2-M transition. Uncontrolled MASTL activity is implicated in breast cancer progression. To date, very few inhibitors have been reported against this protein. Here, structure-based computational modeling indicates that the natural product flavopiridol (FLV) binds strongly to MASTL and these results are validated using molecular dynamics simulation studies. An in vitro kinase assay reveals an EC50 (effective concentration) value of FLV to be 82.1 nM and a better IC50 compared to the positive reference compound, staurosporine. FLV is found to inhibit MASTL kinase activity, arresting the cell growth in the G1 phase and inducing apoptosis in breast cancer cells. Consistent with these results differential gene expression obtained using RNA sequencing studies, and validated by RT PCR and immunoblot analysis, indicate that MASTL inhibition induces cell cycle arrest and apoptotic-related genes. Furthermore, metastasis- and inflammation-related genes are downregulated. Thus, the deregulation of MASTL signaling pathways on targeted inhibition of its kinase activity is revealed. This study lays a strong foundation for investigating FLV as a lead compound in breast cancer therapeutics.
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