Article

THZ1 suppresses human non-small-cell lung cancer cells in vitro through interference with cancer metabolism

Authors: Zhu-Jun Cheng1, Du-Ling Miao1, Qiu-Yun Su2, Xiao-Li Tang2, Xiao-Lei Wang1, Li-Bin Deng1, Hui-Dong Shi1,3, Hong-Bo Xin1
1 Institute of Translational Medicine, Nanchang University, Nanchang 330031, China
2 School of Medicine, Nanchang University, Nanchang 330031, China
3 Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
Correspondence to: Hui-Dong Shi: hshi@augusta.edu, Hong-Bo Xin: hongboxin@yahoo.com,
DOI: 10.1038/s41401-018-0187-3
Received: 18 April 2018
Accepted: 15 October 2018
Advance online: 16 November 2018

Abstract

Cancer cells always require more nutrients, energy, and biosynthetic activity to sustain their rapid proliferation than normal cells. Previous studies have shown the impact of THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), on transcription regulation and cell-cycle arrest in numerous cancers, but its effects on cellular metabolism in cancer cells remain unknown. In this study we elucidated the anticancer mechanism of THZ1 in human non-small-cell lung cancer (NSCLC) cells. We showed that treatment with THZ1 (10−1000 nM) dose-dependently suppressed the proliferation of human NSCLC cell lines H1299, A549, H292, and H23, and markedly inhibited the migration of these NSCLC cells. Furthermore, treatment with THZ1 (50 nM) arrested cell cycle at G2/M phase and induced apoptosis in these NSCLC cell lines. More importantly, we revealed that treatment with THZ1 (50 nM) blocked the glycolysis pathway but had no effect on glutamine metabolism. We further demonstrated that THZ1 treatment altered the expression pattern of glutaminase 1 (GLS1) isoforms through promoting the ubiquitination and degradation of NUDT21. Combined treatment of THZ1 with a glutaminase inhibitor CB-839 (500 nM) exerted a more potent anti-proliferative effect in these NSCLC cell lines than treatment with THZ1 or CB-839 alone. Our results demonstrate that the inhibitory effect of THZ1 on the growth of human NSCLC cells is partially attributed to interfering with cancer metabolism. Thus, we provide a new potential therapeutic strategy for NSCLC treatment by combining THZ1 with the inhibitors of glutamine metabolism.
Keywords: THZ1; CDK7 inhibitor; non-small-cell lung cancer; anti-proliferative effect; cell-cycle arrest; cell apoptosis; glycolysis pathway; glutamine metabolism; CB-839

Article Options

Download Citation

Cited times in Scopus