Cardamonin represses gastric adenocarcinoma development by modulating c-Myc/GLUT4/PGC-1α axis mediated glucose uptake and energy metabolism reprogramming.

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.