WZ35 inhibits gastric cancer cell metastasis by depleting glutathione to promote cellular metabolic remodeling

This study aimed at elucidating the crosstalk between redox reaction and metabolic remodeling through uncovering the mechanism underlying WZ35-mediated reactive oxygen species (ROS) production and regulation of amino acid metabolism to inhibit gastric cancer (GC) cell metastasis. The activity and bi...

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Bibliographic Details
Published in:Cancer letters 2023-02, Vol.555, p.216044-216044, Article 216044
Main Authors: Chen, Tongke, Chen, Junbo, Zeng, Tianni, Huang, Qianying, Chen, Di, Chen, Hong, Chen, Jiayao, Zheng, Bin, Wang, Mengting, Chen, Shinuo, Dai, Jichen, Sun, Hanxiao, Chen, Tongzuan, Huang, Yuwen, Zhao, Liqian, Ma, Shumei, Liu, Xiaodong
Format: Article
Language:English
Subjects:
Apoptosis
Cell Line, Tumor
Curcumin - pharmacology
Glutathione
Glutathione depletion
Humans
Metabolic remodeling
Metastasis
Reactive Oxygen Species - metabolism
ROS-YAP-AXL loop Pathway
Stomach Neoplasms - drug therapy
Stomach Neoplasms - genetics
Stomach Neoplasms - metabolism
Tumor Microenvironment
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Summary:This study aimed at elucidating the crosstalk between redox reaction and metabolic remodeling through uncovering the mechanism underlying WZ35-mediated reactive oxygen species (ROS) production and regulation of amino acid metabolism to inhibit gastric cancer (GC) cell metastasis. The activity and biosafety of curcumin analog, WZ35, were verified in vitro and in vivo. The potential molecular mechanism underlying WZ35-mediated enhanced radiotherapeutic sensitivity by reduced Glutathione (GSH) depletion was elucidated by RNA sequencing, single-cell sequencing (scRNA-seq), metabolic mass spectrometry, and other molecular experiments. Compared to curcumin, WZ35 proved more potent anti-proliferative and anti-metastasis properties. Importantly, we demonstrated that WZ35 could consume GSH in multiple ways, including by reduction of raw materials and consumption reserves, inhibition of reformation, and enhanced decomposition. Mechanistically, we identify that WZ35 maintains the GSH depletion phenotype through the ROS-YAP-AXL-ALKBH5-GLS2 loop, further backing the relevance of metabolic remodeling in the tumor microenvironment with tumor metastasis and the role of m6A in tumor metastasis. Collectively, our study identified WZ35 as a novel GSH depletion agent and a previously undiscovered GSH depletion loop mechanism in GC cell metastasis.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2022.216044