The role of anti-apoptotic Bcl-2 proteins for colorectal cancer development and progression
Final Report Abstract
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”.
Publications
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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 BC, Scherr AL, Lorenz S, Urbanik T, Kautz N, Elssner C, Welte S, Bermejo JL, Jäger D, Schulze-Bergkamen H
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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 BC, Scherr AL, Lorenz S, Elssner C, Kautz N, Welte S, Jaeger D, Urbanik T, Schulze- Bergkamen H
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Targeting cell death signaling in colorectal cancer: current strategies and future perspectives. World J Gastroenterol. 2014 Feb 28
Koehler BC, Jäger D, Schulze-Bergkamen H
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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 BC, Jassowicz A, Scherr AL, Lorenz S, Radhakrishnan P, Kautz N, Elssner C, Weiss J, Jaeger D, Schneider M, Schulze-Bergkamen H
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Bcl-xL is an oncogenic driver in colorectal cancer. Cell Death Dis. 2016 Aug 18
Scherr AL, Gdynia G, Salou M, Radhakrishnan P, Duglova K, Heller A, Keim S, Kautz N, Jassowicz A, Elssner C, He YW, Jaeger D, Heikenwalder M, Schneider M, Weber A, Roth W, Schulze-Bergkamen H, Koehler BC
