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

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.

Association Between Sleep Duration and Stroke in Different Status of Metabolic Syndrome: A Cross-Sectional Study in Shanghai Adult Residents.

Purpose: This study aimed to investigate the relationship between sleep duration (SD) and stroke, and examine the effects of SD on stroke with or without metabolic syndrome (Mets) and its components among the adult residents in Shanghai, China. Participants and Methods: A total of 20,245 participants (51.72% male, mean age 44.66 years) were included from Shanghai Chronic Disease and Risk Factors Surveillance (SCDRFS) in 2017. The weighted logistic regressions were performed to examine the associations between SD and stroke in different status of Mets and its components. Results: The mean SD was 7.51±0.03 h/d. After adjusting for all the potential factors, SD<6 h/d (OR=1.73, 95% CI: 1.35-2.20) or ≥10 h/d (OR=1.66, 95% CI: 1.08-2.57) was significantly positively associated with stoke in the total participants; moreover, in the non-Mets group, only SD<6 h/d (OR=1.77, 95% CI: 1.19, 2.64) significantly increased the risk of stroke; while, in the Mets group, SD<6 h/d (OR=1.80, 95% CI:1.17-2.76) and ≥10 h/d (OR=1.97, 95% CI: 1.00-3.88) both had a positive significantly association with stoke. In addition, the effects of SD<6 h/d on stroke were more pronounced among those with high WC (OR=2.24, 95% CI: 1.40-3.58) and high TG (OR=2.60, 95% CI: 1.86-3.62), and the effects of SD≥10 h/d on stroke were more evident among those with high TG (OR=2.28, 95% CI: 1.02-5.08) and high FBG (OR=2.58, 95% CI: 1.30-5.10). Conclusion: Both short and long SD were significantly positively associated with stroke in the total participants, and the associations were stronger in the Mets group; conversely, in the non-Mets group, only short SD was significantly positively associated with stroke, and no significant association was observed between long SD and stroke. Therefore, more precise sleep measures may be needed to prevent stroke according to the different status of Mets.