Die Rolle von Cdk5 als Target beim hepatozellulären Karzinom
Zusammenfassung der Projektergebnisse
We achieved all specific objectives of our proposal: our project funded by the DFG shows that the expression of Cdk5 is increased in human HCC compared to healthy liver tissue (specific objective 1). Inhibition of Cdk5 by genetic knockdown as well as by pharmacologic inhibition decreased HCC cell proliferation and clonogenic survival. Thus, our study not only extends the limited knowledge about Cdk5 in cancer in general but is novel for HCC. Our mechanistic studies imply a Cdk5 driven signaling which is so far not well characterized in HCC showing that Cdk5 is most active in the nucleus of cells in G2/M phase and that Cdk5 regulates DNA damage response by phosphorylating Ataxia telangiectasia mutated (ATM) kinase (specific objective 2). Consequently, combination of Cdk5 inhibition with DNA damage inducing chemotherapeutics synergistically inhibited HCC tumor progression in vitro and in vivo (specific objective 3). Because of the intrinsic resistance of HCCs as well as dose-limitation due to concomitant liver cirrhosis and co-morbidity, the benefit of DNA damaging agents in HCC therapy is limited and these agents are not commonly used for HCC therapy. Combined administration of Cdk5 inhibitors and DNA damaging agents might reduce effective doses of DNA damaging agents to tolerable concentrations in patients with liver cirrhosis. Thus, our study provides evidence for a promising target and biological circuit to combat HCC: Cdk5 and DNA damage response. In addition, we found a clear relation between angiogenesis in HCC and Cdk5 activity. We identified Ser 687 in the HIF-1α protein a s a novel substrate for Cdk5, regulating the stability of this transcription factor. This signaling pathway plays a role in both, endothelial cells and tumor cells, and can also be connected to the in vivo findings (specific objectives 4 and 5). Finally, we identified s group of pyrazolo[4,3-d]pyrimidines with anti-angiogenic properties and a superior potency, which decreased HCC growth in an in vivo model (specific objective 6). To conclude, we introduce Cdk5 as a novel drugable target for HCC treatment and suggest the combination of Cdk5 inhibition and DNA damaging agents as a novel therapeutic approach for HCC.
Projektbezogene Publikationen (Auswahl)
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Targeting cyclin dependent kinase 5 in hepatocellular carcinoma--A novel therapeutic approach. J Hepatol. 2015;63(1):102-13
Ehrlich SM, Liebl J, Ardelt MA, Lehr T, De Toni EN, Mayr D, Brandl L, Kirchner T, Zahler S, Gerbes AL, Vollmar AM
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Anti-angiogenic effects of novel cyclin-dependent kinase inhibitors with a pyrazolo[4,3-d]pyrimidine scaffold. Br J Pharmacol. 2016;173(17):2645-56
Zhang S, Ulrich M, Gromnicka A, Havlíček L, Kryštof V, Jorda R, Strnad M, Vollmar AM, Zahler S
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Cyclin-dependent kinase 5 stabilizes hypoxia-inducible factor-1α: a novel approach for inhibiting angiogenesis in hepatocellular carcinoma. Oncotarget. 2016;7(19):27108-21
Herzog J, Ehrlich SM, Pfitzer L, Liebl J, Fröhlich T, Arnold GJ, Mikulits W, Haider C, Vollmar AM, Zahler S
