Die Rolle der Polo-like Kinasen1/2 als Mediatoren von Hedgehog-Überlebenssignalen in Cholangiokarzinomzellen
Zusammenfassung der Projektergebnisse
In the present project, we further investigated crosstalks of tumor survival pathways in cholangiocarcinoma (CCA) - a highly malignant and poorly treatable bile duct cancer. Our studies provide new mechanistic insights regarding a hedgehog (Hh)/polo-like kinase (PLK)- signaling co-activation network in CCA. These data indicate that (1) Hh signalling directly regulates PLK2 mRNA and protein expression, (2) PLK2 promotes myeloid cell leukemia-1 (Mcl-1) stabilization (via inhibition of its proteasomal degradation) providing resistance to cell death by tumor necrosis factor related apoptosis inducing ligand (TRAIL), and (3) PLK or Hh inhibition displays proapoptotic effects in an orthotopic syngeneic rodent in vivo CCA model. Thus, members of the cell cycle regulatory PLK protein family were shown to act as an important link between Hh survival signaling and anti-apoptotic Mcl-1 expression in CCA. Despite their clear anti-CCA effects and probable therapeutic values as single-agents, combinations of Hh/PLK inhibitors plus/minus conventional chemotherapeutics did not display enhanced or additive synergistic drug effects on CCA cell lines. Given this unexpected finding, we decided not to further employ our rodent CCA model for these studies. As a surprising finding of this project, PLK3, another member of the PLK protein family, turned out to have a regulatory effect on CCA cell migration. These data indicate that (1) PLK3 is selectively expressed in CCA cells/glands, (2) FGF (e.g., from the tumor stroma) rapidly induces PLK3 mRNA expression in CCA cells, and (3) in contrast to other PLK proteins, PLK3 might be a positive predictor of a favorable clinical course as its expression reduces CCA cell migration (in a NF-κB- and epithelial mesenchymal transition [EMT]-independent manner) and correlates with improved disease-specific overall survival and less invasive tumors of CCA patients. These observations might have implications for prognosis prediction of human CCA as well as the potential therapeutic use of PLK inhibitors (i.e., requirement of PLK1/2 specifity). Moreover, we assume a link between Hh/growth factor signaling and the notch pathway in CCA cells and, thus, have initiated a proteomic analysis. The evaluation of the large data sets generated in these experiments will take more time and might result in a follow-up grant proposal. Finally, parts of the present project were distinguished by an experimental research award (181. NRW-Chirurgiekongress, Bochum, Nov. 2014) and turned out to be extremely helpful for the applicant regarding his admittance into the “Exzellenz-Akademie der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie sowie des Konvents der Lehrstuhlinhaber“ in 2015.
Projektbezogene Publikationen (Auswahl)
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(2013). Expression of Apoptosis- and Vitamin D Pathway-Related Genes in Hepatocellular Carcinoma. Digestion 87(3):176-181
Fingas CD, Altinbas A, Schlattjan M, Beilfuss A, Sowa JP, Sydor S, Bechmann LP, Ertle J, Akkiz H, Herzer K, Paul A, Gerken G, Baba HA, Canbay A
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(2014) Polo-like kinase 2 is a mediator of hedgehog survival signaling in cholangiocarcinoma. Hepatology 58(4):1362-74
Fingas CD, Mertens JC, Razumilava N, Sydor S, Bronk SF, Christensen JD, Rizvi SH, Canbay A, Treckmann JW, Paul A, Sirica AE, Gores GJ
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(2015). Polo-like kinase 3 is associated with improved overall survival in cholangiocarcinoma. Liver Int. 35(11):2448-57
Juntermanns B, Sydor S, Kaiser GM, Jaradat D, Mertens JC, Sotiropoulos GC, Swoboda S, Neuhaus JP, Meng W, Mathé Z, Baba HA, Canbay A, Paul A, Fingas CD
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(2015). Trail receptor deletion suppresses the inflammation of nutrient excess. J Hepatol. 62(5):1156-63
Idrissova L, Malhi H, Werneburg NW, Bronk SF, Fingas CD et al.
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(2016). Novel immunohistochemical markers differentiate intrahepatic cholangiocarcinoma from benign bile duct lesions. J Clin Pathol.
Bertram S, Padden J, Kälsch J, Ahrens M, Pott L, Canbay A, Weber F, Fingas CD et al.
