Atorvastatin Augments Gemcitabine-Mediated Anti-Cancer Effects by Inhibiting Yes-Associated Protein in Human Cholangiocarcinoma Cells
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...
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MDPI AG
2020-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/20/7588 |
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| author | Koh Kitagawa Kei Moriya Kosuke Kaji Soichiro Saikawa Shinya Sato Norihisa Nishimura Tadashi Namisaki Takemi Akahane Akira Mitoro Hitoshi Yoshiji |
| author_facet | Koh Kitagawa Kei Moriya Kosuke Kaji Soichiro Saikawa Shinya Sato Norihisa Nishimura Tadashi Namisaki Takemi Akahane Akira Mitoro Hitoshi Yoshiji |
| author_sort | Koh Kitagawa |
| collection | DOAJ |
| description | 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 <i>BAX</i> and downregulating the anti-apoptotic markers <i>MCL1</i> and <i>BCL2</i>. Atorvastatin also significantly decreased the mRNA expression of the TEAD target genes <i>CTGF</i>, <i>CYR61</i>, <i>ANKRD1</i>, and <i>MFAP5</i> 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. |
| first_indexed | 2024-03-10T15:38:59Z |
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| language | English |
| last_indexed | 2024-03-10T15:38:59Z |
| publishDate | 2020-10-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e79105804f0b410581bff821dec2c3922023-11-20T17:04:25ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-012120758810.3390/ijms21207588Atorvastatin Augments Gemcitabine-Mediated Anti-Cancer Effects by Inhibiting Yes-Associated Protein in Human Cholangiocarcinoma CellsKoh Kitagawa0Kei Moriya1Kosuke Kaji2Soichiro Saikawa3Shinya Sato4Norihisa Nishimura5Tadashi Namisaki6Takemi Akahane7Akira Mitoro8Hitoshi Yoshiji9Department of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, JapanDepartment of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, JapanDepartment of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, JapanDepartment of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, JapanDepartment of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, JapanDepartment of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, JapanDepartment of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, JapanDepartment of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, JapanDepartment of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, JapanDepartment of Gastroenterology and Hepatology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, JapanCholangiocarcinoma (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 <i>BAX</i> and downregulating the anti-apoptotic markers <i>MCL1</i> and <i>BCL2</i>. Atorvastatin also significantly decreased the mRNA expression of the TEAD target genes <i>CTGF</i>, <i>CYR61</i>, <i>ANKRD1</i>, and <i>MFAP5</i> 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.https://www.mdpi.com/1422-0067/21/20/7588atorvastatinHMG-CoA reductasegemcitabineTEAD transcriptional activationyes-associated proteincholangiocarcinoma |
| spellingShingle | Koh Kitagawa Kei Moriya Kosuke Kaji Soichiro Saikawa Shinya Sato Norihisa Nishimura Tadashi Namisaki Takemi Akahane Akira Mitoro Hitoshi Yoshiji Atorvastatin Augments Gemcitabine-Mediated Anti-Cancer Effects by Inhibiting Yes-Associated Protein in Human Cholangiocarcinoma Cells International Journal of Molecular Sciences atorvastatin HMG-CoA reductase gemcitabine TEAD transcriptional activation yes-associated protein cholangiocarcinoma |
| title | Atorvastatin Augments Gemcitabine-Mediated Anti-Cancer Effects by Inhibiting Yes-Associated Protein in Human Cholangiocarcinoma Cells |
| title_full | Atorvastatin Augments Gemcitabine-Mediated Anti-Cancer Effects by Inhibiting Yes-Associated Protein in Human Cholangiocarcinoma Cells |
| title_fullStr | Atorvastatin Augments Gemcitabine-Mediated Anti-Cancer Effects by Inhibiting Yes-Associated Protein in Human Cholangiocarcinoma Cells |
| title_full_unstemmed | Atorvastatin Augments Gemcitabine-Mediated Anti-Cancer Effects by Inhibiting Yes-Associated Protein in Human Cholangiocarcinoma Cells |
| title_short | Atorvastatin Augments Gemcitabine-Mediated Anti-Cancer Effects by Inhibiting Yes-Associated Protein in Human Cholangiocarcinoma Cells |
| title_sort | atorvastatin augments gemcitabine mediated anti cancer effects by inhibiting yes associated protein in human cholangiocarcinoma cells |
| topic | atorvastatin HMG-CoA reductase gemcitabine TEAD transcriptional activation yes-associated protein cholangiocarcinoma |
| url | https://www.mdpi.com/1422-0067/21/20/7588 |
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