Potential conflict of interest: Nothing to report.
Polo-like kinase 2 is a mediator of hedgehog survival signaling in cholangiocarcinoma
Article first published online: 6 AUG 2013
Copyright © 2013 by the American Association for the Study of Liver Diseases
Volume 58, Issue 4, pages 1362–1374, October 2013
How to Cite
Fingas, C. D., Mertens, J. C., Razumilava, N., Sydor, S., Bronk, S. F., Christensen, J. D., Rizvi, S. H., Canbay, A., Treckmann, J. W., Paul, A., Sirica, A. E. and Gores, G. J. (2013), Polo-like kinase 2 is a mediator of hedgehog survival signaling in cholangiocarcinoma. Hepatology, 58: 1362–1374. doi: 10.1002/hep.26484
This work was supported by grants DFG FI 1630/3-1 (CDF), National Institutes of Health (NIH) DK59427 (to G.J.G.), NIH R01 CA 39225 (to A.E.S.), and the optical microscopy and clinical core of NIH DK84567. Mouse anti-S peptide antibody was provided by S.H. Kaufmann (Oncology Research, Mayo Clinic, Rochester, MN).
- Issue published online: 1 OCT 2013
- Article first published online: 6 AUG 2013
- Accepted manuscript online: 22 MAY 2013 10:47AM EST
- Manuscript Accepted: 16 APR 2013
- Manuscript Received: 22 DEC 2012
Cholangiocarcinoma (CCA) cells paradoxically express the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and thus rely on potent survival signals to circumvent cell death by TRAIL. Hedgehog (Hh) signaling is an important survival pathway in CCA. Herein, we further examine the mechanisms whereby Hh signaling mediates apoptosis resistance in CCA, revealing a pivotal role for the cell division regulating serine/threonine kinase polo-like kinase 2 (PLK2). We employed 50 human CCA samples (25 intrahepatic and 25 extrahepatic CCA) as well as human KMCH-1, Mz-CHA-1, and HUCCT-1 CCA cells for these studies. In vivo experiments were conducted using a syngeneic rat orthotopic CCA model. In human samples, polo-like kinase (PLK)1/2/3-immunoreactive cancer cells were present in the preponderance of intra- and extrahepatic CCA specimens. Inhibition of Hh signaling by cyclopamine reduced PLK2, but not PLK1 or PLK3, messenger RNA and protein expression in vehicle-treated and sonic Hh–treated CCA cells, confirming our previous microarray study. PLK2 regulation by Hh signaling appears to be direct, because the Hh transcription factors, glioma-associated oncogene 1 and 2, bind to the PLK2 promotor. Moreover, inhibition of PLK2 by the PLK inhibitor, BI 6727 (volasertib), or PLK2 knockdown was proapoptotic in CCA cells. BI 6727 administration or PLK2 knockdown decreased cellular protein levels of antiapoptotic myeloid cell leukemia 1 (Mcl-1), an effect reversed by the proteasome inhibitor, MG-132. Finally, BI 6727 administration reduced Mcl-1 protein expression in CCA cells, resulting in CCA cell apoptosis and tumor suppression in vivo. Conclusion: PLK2 appears to be an important mediator of Hh survival signaling. These results suggest PLK inhibitors to be of therapeutic value for treatment of human CCA. (Hepatology 2013;58:1362–1374)