The role of cytidine 5′‐triphosphate synthetase 1 in metabolic rewiring during epithelial‐to‐mesenchymal transition in non‐small‐cell lung cancer

Author:

Nakasuka Fumie123ORCID,Hirayama Akiyoshi12,Makinoshima Hideki456,Yano Seiji7,Soga Tomoyoshi12,Tabata Sho1456

Affiliation:

1. Institute for Advanced Biosciences Keio University Tsuruoka Japan

2. Systems Biology Program, Graduate School of Media and Governance Keio University Fujisawa Japan

3. Department of Molecular Pathology, Graduate School of Medicine The University of Tokyo Japan

4. Tsuruoka Metabolomics Laboratory National Cancer Center Tsuruoka Japan

5. Shonai Regional Industry Promotion Center Tsuruoka Japan

6. Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center National Cancer Center Kashiwa Japan

7. Department of Medical Oncology, Kanazawa University Cancer Research Institute Kanazawa University Japan

Abstract

Epithelial‐to‐mesenchymal transition (EMT) contributes to the poor prognosis of patients with cancer by promoting distant metastasis and anti‐cancer drug resistance. Several distinct metabolic alterations have been identified as key EMT phenotypes. In the present study, we further characterize the role of transforming growth factor‐β (TGF‐β)‐induced EMT in non‐small‐cell lung cancer. Our study revealed that TGF‐β plays a role in EMT functions by upregulation of cytidine 5′‐triphosphate synthetase 1 (CTPS), a vital enzyme for CTP biosynthesis in the pyrimidine metabolic pathway. Both knockdown and enzymatic inhibition of CTPS reduced TGF‐β‐induced changes in EMT marker expression, chemoresistance and migration in vitro. Moreover, CTPS knockdown counteracted the TGF‐β‐mediated downregulation of UDP‐glucuronate, glutarate, creatine, taurine and nicotinamide. These findings indicate that CTPS plays a multifaceted role in EMT metabolism, which is crucial for the malignant transformation of cancer through EMT, and underline its potential as a promising therapeutic target for preventing drug resistance and metastasis in non‐small‐cell lung cancer.

Funder

Kanazawa University

Japan Society for the Promotion of Science

Naito Foundation

Publisher

Wiley

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