Abstract
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.
Highlights
Cholangiocarcinoma (CCA) is an aggressive cancer in bile ducts with a high frequency of recurrence and an extremely poor prognosis
Our results showed the inhibitory effect of avasimibe on CCA in vivo and in vitro and demonstrated that avasimibe targets Forkhead box protein M1 (FoxM1)/Aldo-keto reductase 1 family member C1 (AKR1C1) signaling, an essential pathway in tumorigenesis and cancer progression
To investigate whether FoxM1 could regulate the effects of avasimibe on cholangiocarcinoma cells proliferation, we overexpressed FoxM1 in RBE cells and QBC9393 cells before avasimibe treatment, and we found FoxM1 overexpression could counteract the effects of avasimibe on cholangiocarcinoma cells proliferation (Figures 6A, B)
Summary
Cholangiocarcinoma (CCA) is an aggressive cancer in bile ducts with a high frequency of recurrence and an extremely poor prognosis. Numerous risk factors induce CCA, including primary sclerosing cholangitis, parasitic infections and choledochal cysts [4]. Avasimibe Interrupts Cholangiocarcinoma Progression curative for CCA patients diagnosed at early-stage disease. For patients with advanced-stage or unresectable CCA, the effectiveness of systemic therapies is limited, and the median overall survival is less than one year [5]. Recent progress in molecular genetics provide one avenue to develop pharmacological inhibitors of pathologic mutations. Whether patients with advanced CCA could obtain a benefit from genetic profiling and classifications underlying CCA tumorigenesis, as well as screening more effective therapeutic strategies, including conventional chemotherapy, radiotherapy, targeted therapies, and immunotherapy remain largely unclarified
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