Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 954, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2023.175856
Keywords
Warburg effect; PKM2; Oridonin; Colorectal cancer
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Our study first shows that ORI could have anticancer activity by inhibiting the Warburg effect as a novel activator of PKM2.
Background: The Warburg effect is prevalent in human cancer. Oridonin (ORI) has excellent anticancer effects, but its exact anticancer mechanism is still unclear.Methods: CCK8, EdU, and flow cytometry assay were performed to detect the effect of ORI on cell viability, proliferation and apoptosis, respectively. RNA-seq was carried out to search the underlying mechanisms. Total PKM2, dimeric PKM2, nuclear PKM2 was detected by Western blot. The epidermal growth factor receptor/ extracellular signal regulated kinase (EGFR/ERK) signaling was assayed. The binding ability of Importin-& alpha;5 to PKM2 was performed by Co-IP experiments. The effect of ORI combined with cysteine (Cys) or fructose-1, 6diphosphate (FDP) on cancer cells was detected. Mouse xenograft model was established to confirm the molecular mechanisms in vivo.Results: ORI inhibited viability, proliferation and promoted apoptosis of CRC cells. RNA-seq revealed ORI attenuated the Warburg effect in cancer cells. ORI reduced dimeric PKM2 and prevented it from entering the nucleus. ORI did not affect the EGFR/ERK signaling, but reduced Importin-& alpha;5 binding to the PKM2 dimer. Cys or FDP reversed or enhanced the effect of ORI. Animal model assay confirmed the molecular mechanisms in vivo.Conclusions: Our study first shows that ORI could have anticancer activity by inhibiting the Warburg effect as a novel activator of PKM2.
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