Bcl-x(L) as prognostic marker and potential therapeutic target in cholangiocarcinoma

Hoffmeister-Wittmann, Paula; Mock, Andreas; Nichetti, Federico; Korell, Felix; Heilig, Christop E.; Scherr, Anna-Lena; Gunther, Michael; Albrecht, Thomas; Kelmendi, Eblina; Xu, Kaiyu; Nader, Luisa; Kessler, Annika; Schmitt, Nathalie; Fritzsche, Sarah; Weiler, Sofia; Sobol, Benjamin; Stenzinger, Albrecht; Boeck, Stefan; Westphalen, Christoph B.; Schulze-Osthoff, Klaus; Trojan, Jörg; Kindler, Thomas; Weichert, Wilko; Spiekermann, Karsten; Bitzer, Michael; Folprecht, Gunnar; Illert, Anna-Lena; Boerries, Melanie; Klauschen, Frederick; Ochsenreiter, Sebastian; Siveke, Jens; Bauer, Sebastian; Glimm, Hanno; Brors, Benedikt; Huellein, Jennifer; Huebschmann, Daniel; Uhrig, Sebastian; Horak, Peter; Kreutzfeld, Simon; Banales, Jesus M.; Springfeld, Christoph; Jaeger, Dirk; Schirmacher, Peter; Roessler, Stephanie; Ormanns, Steffen; Goeppert, Benjamin; Froehling, Stefan und Koehler, Bruno C. (2022): Bcl-x(L) as prognostic marker and potential therapeutic target in cholangiocarcinoma. In: Liver International, Bd. 42, Nr. 12: S. 2855-2870

Abstract

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-x(L), 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-x(L) and Mcl-1. Expression of Bcl-x(L), 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-x(L) and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatemnt with specific small molecule inhibitors of Bcl-x(L) (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-x(L) induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-x(L) 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-x(L) in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-x(L) as a key protein in cell death resistance of CCA and may pave the way for clinical application.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1478-3223
• Sprache: Englisch