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Please use this identifier to cite or link to this item: http://hdl.handle.net/10564/3902

Title: Atorvastatin Augments Gemcitabine-Mediated Anti-Cancer Effects by Inhibiting Yes-Associated Protein in Human Cholangiocarcinoma Cells.
Other Titles: スタチンはYAP制御を介してゲムシタビンの肝内胆管癌抑制効果を増強させる
Authors: Kitagawa, Koh
Moriya, Kei
Kaji, Kosuke
Saikawa, Soichiro
Sato, Shinya
Nishimura, Norihisa
Namisaki, Tadashi
Akahane, Takemi
Mitoro, Akira
Yoshiji, Hitoshi
Keywords: atorvastatin
HMG-CoA reductase
gemcitabine
TEAD transcriptional activation
yes-associated protein
cholangiocarcinoma
Issue Date: 14-Oct-2020
Publisher: MDPI
Citation: International journal of molecular sciences Vol.21 No.20 Article No.7588 (2020 Oct)
Abstract: Cholangiocarcinoma (CCA) is associated with high mortality rates because of its resistance to conventional gemcitabine-based chemotherapy. Hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors (statins) reportedly exert anti-cancer effects in CCA and lower the risk of CCA; however, the underlying mechanism of these effects remains unclear. The proliferative and oncogenic activities of the transcriptional co-activator Yes-associated protein (YAP) are driven by its association with the TEA domain (TEAD) of transcription factors; thereby, upregulating genes that promote cell growth, inhibit apoptosis, and confer chemoresistance. This study investigated the effects of atorvastatin in combination with gemcitabine on the progression of human CCA associated with YAP oncogenic regulation. Both atorvastatin and gemcitabine concentration-dependently suppressed the proliferation of HuCCT-1 and KKU-M213 human CCA cells. Moreover, both agents induced cellular apoptosis by upregulating the pro-apoptotic marker BAX and downregulating the anti-apoptotic markers MCL1 and BCL2. Atorvastatin also significantly decreased the mRNA expression of the TEAD target genes CTGF, CYR61, ANKRD1, and MFAP5 in both CCA cell lines. A xenograft tumor growth assay indicated that atorvastatin and gemcitabine potently repressed human CCA cell-derived subcutaneous tumor growth by inhibiting YAP nuclear translocation and TEAD transcriptional activation. Notably, the anti-cancer effects of the individual agents were significantly enhanced in combination. These results indicate that gemcitabine plus atorvastatin could serve as a potential novel treatment option for CCA.
Description: 博士(医学)・甲第778号・令和3年3月15日
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
URI: http://hdl.handle.net/10564/3902
ISSN: 14220067
Academic Degrees and number: 24601A778
Degree-granting date: 2021-03-15
Degree name: 博士(医学)
Degree-granting institutions: 奈良県立医科大学
Appears in Collections:2020年度

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