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Cardamonin represses gastric adenocarcinoma development by modulating c-Myc/GLUT4/PGC-1α axis mediated glucose uptake
Xiaohui Liang1, Yujie Zhang1, Jinmei Jin1
1Research Center of Shanghai Traditional Chinese Medicine Standardization, Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Ethnopharmacological Relevance:
Alpiniakatsumadai Hayata (Caodoukou) is widely used in Formulas of TCM for gastric cancer in clinic. Cardamonin (CDN), a chalcone isolated from Caodoukou, fights against multiple kinds of human cancers.
Aim Of The Study:
Our investigation was aimed to clarify the effect of CDN on gastric adenocarcinoma (GA) growth.
Materials And Methods:
CCK-8 assay, EdU staining and flow cytometry were applied to assess in vitro anti-tumor activity. GA cell xenograft, H&E staining and TUNEL assay were used to evaluate in vivo anti-tumor activity. Western blot, DCFH-DA, L-lactate assay kit, 2-NBDG uptake, Glycolytic rate assay kit, Mito stress test kit, and overexpressing plasmids were used to figure out molecular mechanism of CDN.
Results:
CDN triggered growth inhibition both in GA cells and GA xenograft, mainly manifested by increased apoptotic cells and reduced proliferating cells. RNA-seq indicated CDN modulated glycolysis among central carbon metabolism. CDN significantly downregulated protein abundance of glucose metabolism related proteins; suppressed glucose uptake, GlycoPER, OCR, extracellular/intracellular L-Lactate levels before its cell viability suppression. Overexpression of c-Myc, GLUT4 and PGC-1α antagonized constraints of survival ability, aerobic glycolysis and/or OXPHOS stimulated by CDN in GA cells. GLUT4 modulated glycolysis, OXPHOS, protein expression of MCT1, and prevailed CDN-induced PGC-1α repression. In GA patients, high GLUT4 expression had higher T stage, more lymphatic metastasis, later TNM stage and more Ki67 expression, is also associated with poor overall survival.
Conclusions:
CDN inhibits GA by functionally modulating c-Myc/GLUT4/PGC-1α axis mediated glucose uptake and energy metabolism reprogramming, implicating its potential for GA chemotherapy.
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