Abstract
Helichrysetin (HEL), a chalcone isolated from Alpinia katsumadai Hayata, has an antitumor activity in human lung and cervical cancers. However, the inhibitory effect and underlying mechanism of HEL in gastric cancer have not been elucidated. Here, HEL significantly inhibited the growth of gastric cancer MGC803 cells in vitro and in vivo. HEL decreased expression and transcriptional regulatory activity of c-Myc and mRNA expression of c-Myc target genes. HEL enhanced mitochondrial oxidative phosphorylation (OXPHOS) and reduced glycolysis as evidenced by increased mitochondrial adenosine triphosphate (ATP) production and excessive reactive oxygen species (ROS) accumulation, and decreased the pPDHA1/PDHA1 ratio and Glyco-ATP production. Pyruvate enhanced OXPHOS after HEL treatment. c-Myc overexpression abolished HEL-induced inhibition of cell viability, glycolysis, and protein expression of PDHK1 and LDHA. PDHK1 overexpression also counteracted inhibitory effect of HEL on cell viability. Conversely, c-Myc siRNA decreased cell viability, glycolysis, and PDHK1 expression. NAC rescued the decrease in viability of HEL-treated cells. Additionally, HEL inhibited the overactivated mTOR/p70S6K pathway in vitro and in vivo. HEL-induced cell viability inhibition was counteracted by an mTOR agonist. mTOR inhibitor also decreased cell viability. Similar results were obtained in SGC7901 cells. HEL repressed lactate production and efflux in MGC803 cells. These results revealed that HEL inhibits gastric cancer growth by targeting mTOR/p70S6K/c-Myc/PDHK1-mediated energy metabolism reprogramming in cancer cells. Therefore, HEL may be a potential agent for gastric cancer treatment by modulating cancer energy metabolism reprogramming.
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Acknowledgements
Special thanks to Prof. Weidong Zhang (SHUTCM) for providing key apparatus for the measurement of mitochondrial energy metabolism. Great thanks to Prof. Jingshan Shen (Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China) for giving us HEL for research.
Funding
This work was supported by Shanghai Municipal Natural Science Foundation (21ZR1462800); Educational Commission of Shanghai of China (2020LK014, 18LK015); the National Natural Science Foundation of China (81603354); Graduate Student Innovation Ability Project of Shanghai University of Traditional Chinese Medicine (Y2020030, Y2021088), Shanghai E-research Institute of Bioactive Constituent in TCM plan and the Opening Project of Shanghai Key Laboratory of Compound Chinese Medicines (17DZ2273300).
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PW and JMJ did most of experiments and wrote the original draft. XHL took part in finishing cell metabolism assays and Western blotting assay. MZY took part in cell culture and Western blotting assay for manuscript revision. CY took part in cell culture and Western blotting assay. FH and XYF took part in Annexin/PI staining. HW supported to optimize experimental protocols. ZTW and RX gave valuable suggestion for this manuscript. HLS and XJW designed experiments and wrote the manuscript. All authors read and approved the final manuscript.
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All animal experiments were carried out in accordance with the protocol approved by the Animal Ethics Committee in Shanghai University of Traditional Chinese Medicine (SHUTCM), which complies with international rules and policies for laboratory animal use and care as founded in the European Community guidelines (EEC Directive of 1986; 86/609/EEC). All animal experiments were approved by the institutional Ethics Committee of SHUTCM (SZY20160914).
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Wang, P., Jin, Jm., Liang, Xh. et al. Helichrysetin inhibits gastric cancer growth by targeting c-Myc/PDHK1 axis-mediated energy metabolism reprogramming. Acta Pharmacol Sin 43, 1581–1593 (2022). https://doi.org/10.1038/s41401-021-00750-0
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DOI: https://doi.org/10.1038/s41401-021-00750-0
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