PKC signal amplification suppresses non-small cell lung cancer growth by promoting p21 expression and phosphorylation. Issue 9 (September 2022)

• Record Type: Journal Article
• Authors: Liu, Shuyan; Zhang, Yayun; Yang, Qianyi; Zhang, Yingqiu; Liu, Han; Huang, Mu-Hua; Wang, Ruoyu; Lu, Faqiang
• Is Part Of: Heliyon. Volume 8:Issue 9(2022)
• Publication Date: 2022-09
• Subjects: PKC -- Bisindolylmaleimide derivative -- BD-15 -- p21 -- Phosphorylation -- NSCLC; Research -- Periodicals; Medical sciences -- Periodicals; Natural history -- Periodicals; Social sciences -- Periodicals; Earth sciences -- Periodicals; Physical sciences -- Periodicals; 507.2
• DOI: 10.1016/j.heliyon.2022.e10657
• Languages: English
• ISSNs: 2405-8440

Abstract

Abstract: 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 bisindolylmaleimide derivative (3, 4-bis(1-(prop-2-ynyl)-1 H -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 suppress 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. Abstract : PKC; Bisindolylmaleimide derivative; BD-15; p21; Phosphorylation; NSCLC.