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

Zhu Jun Cheng, Du Ling Miao, Qiu Yun Su, Xiao Li Tang, Xiao Lei Wang, Li Bin Deng, Huidong Shi, Hong Bo Xin

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)814-822
Number of pages9
JournalActa Pharmacologica Sinica
Volume40
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Non-Small Cell Lung Carcinoma
Neoplasms
Glutaminase
Glutamine
Cell Line
Cyclin-Dependent Kinases
G2 Phase
Ubiquitination
Glycolysis
Cell Cycle Checkpoints
In Vitro Techniques
Cell Division
Cell Cycle
Protein Isoforms
Cell Proliferation
Apoptosis
Food
Growth

Keywords

  • CB-839
  • CDK7 inhibitor
  • THZ1
  • anti-proliferative effect
  • cell apoptosis
  • cell-cycle arrest
  • glutamine metabolism
  • glycolysis pathway
  • non-small-cell lung cancer

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Cheng, Z. J., Miao, D. L., Su, Q. Y., Tang, X. L., Wang, X. L., Deng, L. B., ... Xin, H. B. (2019). THZ1 suppresses human non-small-cell lung cancer cells in vitro through interference with cancer metabolism. Acta Pharmacologica Sinica, 40(6), 814-822. https://doi.org/10.1038/s41401-018-0187-3

THZ1 suppresses human non-small-cell lung cancer cells in vitro through interference with cancer metabolism. / Cheng, Zhu Jun; Miao, Du Ling; Su, Qiu Yun; Tang, Xiao Li; Wang, Xiao Lei; Deng, Li Bin; Shi, Huidong; Xin, Hong Bo.

In: Acta Pharmacologica Sinica, Vol. 40, No. 6, 01.06.2019, p. 814-822.

Research output: Contribution to journalArticle

Cheng, Zhu Jun ; Miao, Du Ling ; Su, Qiu Yun ; Tang, Xiao Li ; Wang, Xiao Lei ; Deng, Li Bin ; Shi, Huidong ; Xin, Hong Bo. / THZ1 suppresses human non-small-cell lung cancer cells in vitro through interference with cancer metabolism. In: Acta Pharmacologica Sinica. 2019 ; Vol. 40, No. 6. pp. 814-822.
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AU - Miao, Du Ling

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AU - Wang, Xiao Lei

AU - Deng, Li Bin

AU - Shi, Huidong

AU - Xin, Hong Bo

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