RRC ID 54034
Author Saikawa S, Kaji K, Nishimura N, Seki K, Sato S, Nakanishi K, Kitagawa K, Kawaratani H, Kitade M, Moriya K, Namisaki T, Mitoro A, Yoshiji H.
Title Angiotensin receptor blockade attenuates cholangiocarcinoma cell growth by inhibiting the oncogenic activity of Yes-associated protein.
Journal Cancer Lett
Abstract Cholangiocarcinoma (CCA) is a destructive malignancy with limited responsiveness to conventional chemotherapy. Although angiotensin receptor blockers (ARBs) have gained attention for their potential anticancer activity, little is known about their effects on CCA. The transcriptional co-activator, Yes-associated protein (YAP) is a critical oncogene in several cancers, including CCA. Following recent evidence showing that YAP is regulated by angiotensin II (AT-II), we investigated the effects of an ARB, losartan, on two human CCA cell lines (KKU-M213 and HuCCT-1) with regards to YAP oncogenic regulation. Losartan suppressed AT-II-induced CCA cell proliferation in a dose-dependent manner, induced apoptosis, decreased YAP (Ser127), and downregulated the YAP target genes CTGF, CYR61, ANKRD1, and MFAP5. However, losartan did not affect epithelial-mesenchymal transition, differentiation, or stemness in the CCA cells. Xenograft tumor growth assay showed that oral administration of a low clinical dose of losartan considerably reduced subcutaneous tumor burden and attenuated intratumor vascularization in CCA cell-derived xenograft tumors in BALB/c nude mice. These results indicate that ARB therapy could serve as a potential novel strategy for CCA treatment.
Volume 434
Pages 120-129
Published 2018-10-10
DOI 10.1016/j.canlet.2018.07.021
PII S0304-3835(18)30479-8
PMID 30031758
MeSH Adaptor Proteins, Signal Transducing / antagonists & inhibitors* Adaptor Proteins, Signal Transducing / metabolism Angiotensin Receptor Antagonists / pharmacology Animals Bile Duct Neoplasms / drug therapy* Bile Duct Neoplasms / genetics Bile Duct Neoplasms / metabolism Cell Line, Tumor Cell Proliferation / drug effects* Cell Proliferation / genetics Cholangiocarcinoma / drug therapy* Cholangiocarcinoma / genetics Cholangiocarcinoma / metabolism Gene Expression Regulation, Neoplastic / drug effects Humans Losartan / pharmacology* Male Mice, Inbred BALB C Mice, Nude Phosphoproteins / antagonists & inhibitors* Phosphoproteins / metabolism Proto-Oncogenes Transcription Factors Xenograft Model Antitumor Assays* YAP-Signaling Proteins
IF 7.36
Times Cited 6
Human and Animal Cells Hep G2(RCB1886)