The role of anti-apoptotic Bcl-2 proteins for colorectal cancer development and progression
Zusammenfassung der Projektergebnisse
Taken together, the performed in vitro experiments show that anti-apoptotic Bcl-2 proteins are dysregulated in human CRC and that they influence tumor-relevant processes beyond cell death regulation. Mcl-1, which gets downregulated in the course of malignant transformation, seems the only one among the group of anti-apoptotic Bcl-2 proteins that plays an anti-proliferative role in CRC cells. Its loss might be beneficial for transforming cells even if this happens on the expense of cell death prevention. Furthermore, all anti-apoptotic Bcl-2 proteins have been shown to promote the migratory ability and invasiveness of CRC cells with the strongest phenotypes observed for Bcl-2. The generated intestine-specific knockout mouse models revealed a strong discrepancy between Bcl-xL and Mcl-1 with regard to their role for the maintenance of intestinal tissue homeostasis and for colorectal cancer development and progression. Bcl-xL, which seems dispensable for normal tissue homeostasis, was found to be a crucial factor for colorectal cancer cell survival, what confers a tumor-promoting property and explains the overexpression of Bcl-xL in human adenomas and adenocarcinomas. The loss of Mcl-1, by contrast, causes a severe intestinal phenotype, including high levels of apoptotic IECs and massive inflammation. The spontaneous tumorigenesis in Mcl-1ΔIEC mice is promoted by the loss of the anti-proliferative effect Mcl-1 exerts on IECs and by the inflammatory environment, what confers Mcl-1 tumor-suppressing properties and explains its downregulation in human adenomas and adenocarcinomas. For clinical application, it is thus highly recommended to utilize Mcl-1 sparing inhibitors. In the presented project, a first step in this direction was done by treating human CRC tissue ex vivo with the Bcl-xL/Bcl-2 specific BH3 mimetic ABT-737. The results are promising and show a markedly decreased viability of tumor cells even in absence of an additional chemotherapeutic agent. Finally, this project already led to a positive evaluation of a follow-up project entitled “The role of Mcl-1 for intestinal mucosa homeostasis and the colorectal carcinogenesis”.
Projektbezogene Publikationen (Auswahl)
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Beyond cell death - antiapoptotic Bcl-2 proteins regulate migration and invasion of colorectal cancer cells in vitro. PLoS One. 2013 Oct 3
Koehler, Bruno Christian; Scherr, Anna-Lena; Lorenz, Stephan; Urbanik, Toni; Kautz, Nicole; Elssner, Christin; Welte, Stefan; Bermejo, Justo Lorenzo; Jäger, Dirk & Schulze-Bergkamen, Henning
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Pan-Bcl-2 inhibitor obatoclax delays cell cycle progression and blocks migration of colorectal cancer cells. PLoS One. 2014 Sep 5
Koehler, Bruno Christian; Scherr, Anna-Lena; Lorenz, Stephan; Elssner, Christin; Kautz, Nicole; Welte, Stefan; Jaeger, Dirk; Urbanik, Toni & Schulze-Bergkamen, Henning
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Targeting cell death signaling in colorectal cancer: current strategies and future perspectives. World J Gastroenterol. 2014 Feb 28
Koehler, Bruno Christian
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Pan-Bcl-2 inhibitor Obatoclax is a potent late stage autophagy inhibitor in colorectal cancer cells independent of canonical autophagy signaling. BMC Cancer. 2015 Nov 19
Koehler, Bruno Christian; Jassowicz, Adam; Scherr, Anna-Lena; Lorenz, Stephan; Radhakrishnan, Praveen; Kautz, Nicole; Elssner, Christin; Weiss, Johanna; Jaeger, Dirk; Schneider, Martin & Schulze-Bergkamen, Henning
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Bcl-xL is an oncogenic driver in colorectal cancer. Cell Death Dis. 2016 Aug 18
Scherr, Anna-Lena; Gdynia, Georg; Salou, Mariam; Radhakrishnan, Praveen; Duglova, Katarina; Heller, Anette; Keim, Sophia; Kautz, Nicole; Jassowicz, Adam; Elssner, Christin; He, You-Wen; Jaeger, Dirk; Heikenwalder, Mathias; Schneider, Martin; Weber, Achim; Roth, Wilfried; Schulze-Bergkamen, Henning & Koehler, Bruno Christian
