PKC signal amplification suppresses non-small cell lung cancer growth by promoting p21 expression and phosphorylation

Shuyan Liu; Yayun Zhang; Qianyi Yang; Yingqiu Zhang; Han Liu; Mu-Hua Huang; Ruoyu Wang; Faqiang Lu

doi:10.1016/j.heliyon.2022.e10657

PKC signal amplification suppresses non-small cell lung cancer growth by promoting p21 expression and phosphorylation

Heliyon. 2022 Sep 17;8(9):e10657. doi: 10.1016/j.heliyon.2022.e10657. eCollection 2022 Sep.

Authors

Shuyan Liu^{1

2}, Yayun Zhang², Qianyi Yang², Yingqiu Zhang², Han Liu², Mu-Hua Huang³, Ruoyu Wang¹, Faqiang Lu¹

Affiliations

¹ Affiliated Zhongshan Hospital of Dalian University, Dalian, China.
² Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
³ School of Materials Science and Engineering, Beijing Institute of Technology, Beijing, China.

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)-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 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.

Keywords: BD-15; Bisindolylmaleimide derivative; NSCLC; PKC; Phosphorylation; p21.