The curcumin analogue WZ35 affects glycolysis inhibition of gastric cancer cells through ROS-YAP-JNK pathway.

Abstract

To investigate the anti-tumor activities of WZ35 and its possible molecular mechanism, bioinformatics analysis and the hematoxylin-eosin (HE) staining were applied to evaluate the Yes-associated-protein (YAP) level in gastric cancer. Cell counting kit-8 (CCK-8) was used to examine cell viability. Apoptosis was determined by flow cytometry analysis. Seahorse bioenergetics analyzer was used to investigate the alteration of oxygen consumption and aerobic glycolysis rate. SiRNA transfection was applied to silence endogenous YAP. Western blot was performed to detect indicated proteins. We found that treatment of gastric cancer cells with WZ35 exerted stronger anti-tumor activities than curcumin. Mechanistically, our research showed that WZ35 inhibited glycolysis, and induced reactive oxygen species (ROS) generation, resulting in Jun N-terminal Kinase (JNK) activation through downregulation of YAP in gastric cancer cells. ROS mediated YAP downregulation and JNK activation was regulated by glycolysis. Abrogation of ROS production markedly attenuated WZ35 induced anti-tumor activities as well as YAP downregulation and JNK activation. Similarly, the JNK inhibitor significantly reversed WZ35 induced anti-tumor activities in gastric cancer cells. Our study reveals a novel anti-gastric cancer mechanism of WZ35 by inhibiting glycolysis through the ROS-YAP-JNK pathway. WZ35 might be a potential therapeutics for the treatment of gastric cancer.

• Authors: Tongke Chen, Liqian Zhao, Shinuo Chen, Bin Zheng, Hong Chen, Tianni Zeng, Hanxiao Sun, Sijia Zhong, Wencan Wu, Xiaokun Lin, Lihua Wang
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 137 Pg. 111131 (Mar 2020) ISSN: 1873-6351 [Electronic] England
• PMID: 31958483 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Reactive Oxygen Species
• Transcription Factors
• WZ35 compound
• YAP-Signaling Proteins
• YAP1 protein, human
• MAP Kinase Kinase 4
• Curcumin

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Curcumin (analogs & derivatives, pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glycolysis (drug effects)
• Humans
• MAP Kinase Kinase 4 (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Stomach Neoplasms (enzymology, genetics, metabolism, physiopathology)
• Transcription Factors (genetics, metabolism)
• YAP-Signaling Proteins