期刊
HELIYON
卷 8, 期 9, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.heliyon.2022.e10657
关键词
PKC; Bisindolylmaleimide derivative; BD-15; p21; Phosphorylation; NSCLC
资金
- China Postdoctoral Science Foundation [2020M680921]
- National Natural Science Foundation of China [82103146]
This study discovered that a compound named BD-15 exerted anti-tumor effects by enhancing PKC signaling, resulting in cell growth inhibition, cell cycle arrest, upregulation and phosphorylation of p21, and induction of cellular apoptosis in non-small cell lung cancer.
Protein kinase C (PKC) activation was previously associated with oncogenic features. However, small molecule inhibitors targeting PKC have so far proved ineffective in a number of clinical trials for cancer treatment. Recent progresses have revealed that most PKC mutations detected in diverse cancers actually lead to loss-of-function, thus suggesting the tumor-suppressive roles of PKC proteins. Unfortunately, the development of chemicals to enhance PKC activity is lagging behind relative to its small molecular inhibitors. Here, we report that a bisin-dolylmaleimide derivative (3,4-bis(1-(prop-2-ynyl)-1H-indol-3-yl)-1 H-pyrrole-2,5-dione, BD-15) significantly inhibited cell growth in non-small cell lung cancer (NSCLC). Mechanistically, BD-15 treatment resulted in markedly enhanced phosphorylation of PKC substrates and led to cell cycle arrest in G2/M. Further, BD-15 treatment upregulated p21 protein levels and enhanced p21 phosphorylation. BD-15 also promoted caspase3 cleavage and triggered cellular apoptosis. In xenograft mouse models, BD-15 exerted anti-tumor effects to sup-press in vivo tumor formation. Collectively, our findings revealed the tumor-suppressive roles of BD-15 through enhancing PKC signaling and thus leading to upregulation of p21 expression and phosphorylation.
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