Saikosaponin D reverses epinephrine-and norepinephrineinduced gemcitabine resistance in intrahepatic cholangiocarcinoma by downregulating ADRB2/glycolysis signaling  

作　　者：Hui He Jiaqi Guo Yunxiang Hu Han Zhang Xinyang Li Jian Zhang Shi Jin 

机构地区：[1]Department of Laparoscopic Surgery,the First Affiliated Hospital of Dalian Medical University,Dalian 116000,China [2]Department of Interventional Therapy,the First Affiliated Hospital of Dalian Medical University,Dalian 116000,China

出　　处：《Acta Biochimica et Biophysica Sinica》2023年第9期1404-1414,共11页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the National Natural Science Foundation of China(No.81903964 to H.H.and No.82174133 to S.J.).

摘　　要：Intrahepatic cholangiocarcinoma(iCCA)is a highly fatal malignancy with rapidly increasing incidence and mortality worldwide.Currently,gemcitabine-based systemic chemotherapy is the main clinical therapeutic regimen;however,its efficacy is poor,and its mechanism has not been elucidated.In this study,we use a Seahorse Extracellular Flux analyser to measure glycolysis capacity(extracellular acidification rate,ECAR)and oxygen consumption rate(OCR).The glucose uptake or lactic acid content is detected,and the effects of saikosaponin D,an active compound derived from Bupleuri Radix(a traditional Chinese medicine for soothing the liver and relieving depression),on gemcitabine cytotoxicity in norepinephrine-stimulated iCCA cells are analysed.We find that adrenergic signaling plays a fundamental role in chronic stress-induced therapeutic resistance in iCCA.Norepinephrine(NE)and epinephrine(E)enhance the proliferation of iCCA cells and interfere with the response to gemcitabine through activation of theβ2-adrenergic receptor(ADRB2).Furthermore,we find that NE upregulates the expressions of several drug efflux-related genes(such as ABCG2 and MDR1)and promotes glycolysis in iCCA cells.In addition,saikosaponin D reverses the poor response of iCCA cells to gemcitabine by downregulating ADRB2 level.Furthermore,saikosaponin D inhibits drug efflux and glycolysis in iCCA cells by regulating the expressions of MDR1,ABCG2,HK2,and GLUT1.Collectively,saikosaponin D enhances the antitumor effect of gemcitabine by controlling glucose metabolism and drug efflux by inhibiting the ADRB2 signaling.Therefore,the combination of saikosaponin D and gemcitabine may be a potential therapeutic strategy for the treatment of iCCA.

关 键 词：saikosaponin D gemcitabine resistance intrahepatic cholangiocarcinoma ADRB2 GLYCOLYSIS 

分 类 号：R73[医药卫生—肿瘤]