Avasimibe Dampens Cholangiocarcinoma Progression by Inhibiting FoxM1-AKR1C1 Signaling.
Avasimibe Dampens Cholangiocarcinoma Progression by Inhibiting FoxM1-AKR1C1 Signaling.
复制标题
DOI：
10.3389/fonc.2021.677678
复制
发表时间：
2021
影响因子：
4.7
通讯作者：
Yu G
中科院分区：
文献类型：
--
作者：
Gao Y;Xu D;Li H;Xu J;Pan Y;Liao X;Qian J;Hu Y;Yu G
Avasimibe是一种生物可利用的乙酰辅酶A乙酰转移酶（ACAT）抑制剂，在多种人类实体瘤中显示出良好的抗肿瘤作用，但其在胆管癌（CCA）中的治疗价值及其潜在机制在很大程度上尚不清楚。本研究证实了avasimibe对CCA细胞增殖和肿瘤生长有抑制作用，并确定FoxM 1/AKR 1C 1轴为avasimibe潜在的新靶点。醛酮还原酶1家族成员C1（AKR 1C 1）沿着疾病进展而逐渐增加，并在人CCA中高表达。从生存分析来看，AKR 1C 1可能是肿瘤复发和预后的重要预测因子。增强的叉头盒蛋白M1（FoxM 1）表达导致AKR 1C 1的上调，而沉默FoxM 1则相反。FoxM 1直接与AKR 1C 1启动子结合并触发其转录，而FoxM 1结合位点突变降低AKR 1C 1启动子活性。此外，过表达外源FoxM 1逆转了阿伐麦布给药诱导的CCA细胞生长迟缓，而在FoxM 1过表达中沉默AKR 1C 1再次延缓细胞生长。此外，FoxM 1的表达与人类CCA标本中AKR 1C 1的表达显著相关。我们的研究表明，FoxM 1和AKR 1C 1之间的一种新的正调控机制有助于CCA的细胞生长和肿瘤进展，而阿伐麦贝可能是通过靶向该FoxM 1/AKR 1C 1信号通路治疗CCA的一种替代治疗选择。
Avasimibe is a bioavailable acetyl-CoA acetyltransferase (ACAT) inhibitor and shows a good antitumor effect in various human solid tumors, but its therapeutic value in cholangiocarcinoma (CCA) and underlying mechanisms are largely unknown. In the study, we proved that avasimibe retard cell proliferation and tumor growth of CCAs and identified FoxM1/AKR1C1 axis as the potential novel targets of avasimibe. Aldo-keto reductase 1 family member C1 (AKR1C1) is gradually increased along with the disease progression and highly expressed in human CCAs. From survival analysis, AKR1C1 could be a vital predictor of tumor recurrence and prognostic factor. Enforced Forkhead box protein M1 (FoxM1) expression results in the upregulation of AKR1C1, whereas silencing FoxM1 do the opposite. FoxM1 directly binds to promoter of AKR1C1 and triggers its transcription, while FoxM1-binding site mutation decreases AKR1C1 promoter activity. Moreover, over-expressing exogenous FoxM1 reverses the growth retardation of CCA cells induced by avasimibe administration, while silencing AKR1C1 in FoxM1-overexpressing again retard cell growth. Furthermore, FoxM1 expression significantly correlates with the AKR1C1 expression in human CCA specimens. Our study demonstrates a novel positive regulatory between FoxM1 and AKR1C1 contributing cell growth and tumor progression of CCA and avasimibe may be an alternative therapeutic option for CCA by targeting this FoxM1/AKR1C1 signaling pathway.
登录
查看更多内容
DOI：
10.1016/j.jsbmb.2014.09.008
发表时间：
2015-07
期刊：
The Journal of steroid biochemistry and molecular biology
影响因子：
--
作者：
Rogers MA;Liu J;Song BL;Li BL;Chang CC;Chang TY
通讯作者：
Chang TY
醛酮还原酶 AKR1C1-AKR1C4：抗癌治疗的功能、调节和干预
影响因子：
5.6
作者：
Zeng CM;Chang LL;Ying MD;Cao J;He QJ;Zhu H;Yang B
通讯作者：
Yang B
影响因子：
4.6
作者：
Matsumoto R;Tsuda M;Yoshida K;Tanino M;Kimura T;Nishihara H;Abe T;Shinohara N;Nonomura K;Tanaka S
通讯作者：
Tanaka S
DOI：
10.1634/theoncologist.2015-0446
发表时间：
2016-05
期刊：
The oncologist
影响因子：
--
作者：
Saha SK;Zhu AX;Fuchs CS;Brooks GA
通讯作者：
Brooks GA
DOI：
10.2147/lctt.s90694
发表时间：
2016
期刊：
Lung Cancer (Auckland, N.Z.)
影响因子：
--
作者：
Tian H;Li X;Jiang W;Lv C;Sun W;Huang C;Chen R
通讯作者：
Chen R