Bcl-xL as prognostic marker and potential therapeutic target in cholangiocarcinoma
© 2022 The Authors. Liver International published by John Wiley & Sons Ltd..
Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-xL , Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-xL and Mcl-1. Expression of Bcl-xL , Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-xL and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatment with specific small molecule inhibitors of Bcl-xL (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-xL induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-xL and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-xL in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-xL as a key protein in cell death resistance of CCA and may pave the way for clinical application.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:42 |
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| Enthalten in: |
Liver international : official journal of the International Association for the Study of the Liver - 42(2022), 12 vom: 03. Dez., Seite 2855-2870 |
| Sprache: |
Englisch |
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| Links: |
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| Themen: |
Apoptosis |
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| Anmerkungen: |
Date Completed 26.01.2023 Date Revised 26.01.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/liv.15392 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Hoffmeister-Wittmann, Paula |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Bcl-xL as prognostic marker and potential therapeutic target in cholangiocarcinoma |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022 The Authors. Liver International published by John Wiley & Sons Ltd. | ||
| 520 | |a Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-xL , Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-xL and Mcl-1. Expression of Bcl-xL , Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-xL and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatment with specific small molecule inhibitors of Bcl-xL (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-xL induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-xL and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-xL in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-xL as a key protein in cell death resistance of CCA and may pave the way for clinical application | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Bcl-2 | |
| 650 | 4 | |a Bcl-xL | |
| 650 | 4 | |a Mcl-1 | |
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| 650 | 7 | |a Proto-Oncogene Proteins c-bcl-2 |2 NLM | |
| 700 | 1 | |a Mock, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Nichetti, Federico |e verfasserin |4 aut | |
| 700 | 1 | |a Korell, Felix |e verfasserin |4 aut | |
| 700 | 1 | |a Heilig, Christoph E |e verfasserin |4 aut | |
| 700 | 1 | |a Scherr, Anna-Lena |e verfasserin |4 aut | |
| 700 | 1 | |a Günther, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Albrecht, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Kelmendi, Eblina |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Kaiyu |e verfasserin |4 aut | |
| 700 | 1 | |a Nader, Luisa |e verfasserin |4 aut | |
| 700 | 1 | |a Kessler, Annika |e verfasserin |4 aut | |
| 700 | 1 | |a Schmitt, Nathalie |e verfasserin |4 aut | |
| 700 | 1 | |a Fritzsche, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Weiler, Sofia |e verfasserin |4 aut | |
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| 700 | 1 | |a Stenzinger, Albrecht |e verfasserin |4 aut | |
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| 700 | 1 | |a Glimm, Hanno |e verfasserin |4 aut | |
| 700 | 1 | |a Brors, Benedikt |e verfasserin |4 aut | |
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