巴基斯坦卢比
瓦博格效应
MAPK/ERK通路
细胞凋亡
癌症研究
化学
癌细胞
生物
信号转导
细胞生物学
分子生物学
癌症
生物化学
丙酮酸激酶
糖酵解
遗传学
酶
作者
Fan Chen,Jason Liao,Pinghui Wu,Cheng Li,Yingchao Ma,Linghan Zhang,Xiao-Min Leng,Xiufang Zhu,Zhiping Liu,Fuhua Xie
标识
DOI:10.1016/j.ejphar.2023.175856
摘要
The Warburg effect is prevalent in human cancer. Oridonin (ORI) has excellent anticancer effects, but its exact anticancer mechanism is still unclear. 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-α5 to PKM2 was performed by Co-IP experiments. The effect of ORI combined with cysteine (Cys) or fructose-1, 6-diphosphate (FDP) on cancer cells was detected. Mouse xenograft model was established to confirm the molecular mechanisms in vivo. 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-α5 binding to the PKM2 dimer. Cys or FDP reversed or enhanced the effect of ORI. Animal model assay confirmed the molecular mechanisms in vivo. 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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