Jiedu Sangen decoction inhibits chemoresistance to 5-fluorouracil of colorectal cancer cells by suppressing glycolysis via PI3K/AKT/HIF-1αsignaling pathway

摘要

Drug resistance is a major obstacle in the development of effective colorectal cancer(CRC)therapy.Our study aimed to explore the reversal abilities of Jiedu Sangen decoction(JSD)on the 5-fluorouracil(5-FU)resistance and its underlying molecular mechanisms.Expression changes in HIF-1 of CRC tissues were firstly revealed by bioinformatics analysis.Afterwards,cell viabilities of JSD and 5-FU treatments on 5-FU resistant human colon cancer cells(HCT-8/5-FU)were determined.Expressions of phosphoinositide 3-kinase(PI3K),protein kinase B(AKT)/p-AKT,hypoxia-inducible factor 1(HIF-1α),as well as glycolysis related proteins such as L-lactate dehydrogenase A(LDHA),Glucose transporter type 1(Glut1),Hexokinase 2(HKII),and cysteinyl aspartate specific proteinase(Caspase)family members in HCT-8/5-FU cells,HIF-1αsilenced HCT-8/5-FU cells and tumor tissues were detected by western blotting.HIF-1αwas found over expressed in CRC tissues according to public available datasets in Oncomine.Growth inhibition rates of HCT-8/5-FU cells were increased along with the increase of JSD concentrations.JSD caused down-regulated HIF-1α,PI3K,AKT/p-AKT,HKII and Glut1,as well as up-regulated Caspase3 and Caspase9 in HCT-8/5-FU cells and tumor tissues.In HIF-1αsilenced HCT-8/5-FU cells,synergistic group showed significantly reduced expression levels of PI3K,AKT,p-AKT.Additionally,up-regulated expressions of Caspase6 and Caspase7 were observed.JSD combined with 5-FU also exhibited obvious inhibitory efficiency on tumor growth in vivo.JSD may reverse 5-FU resistance by suppressing glycolysis via PI3K/AKT/HIF-1αsignaling pathway,thereby inhibiting glycolysis and induce apoptosis to enhance anti-tumor activity.