ArticleHepatology (Baltimore, Md.)2013
Polo-like kinase 2 is a mediator of hedgehog survival signaling in cholangiocarcinoma.
Article in Hepatology (Baltimore, Md.), 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 41 citations in OpenAlex.
- Hepatic factor MANF drives hepatocytes reprogramming by detaining cytosolic CK19 in intrahepatic cholangiocarcinoma.Cell death and differentiation · 2025Article
- Hedgehog pathway and cancer: A new area (Review).Oncology reports · 2024Review
- DNA Damage Response Inhibitors in Cholangiocarcinoma: Current Progress and Perspectives.Cells · 2022Review
- PD-L1 promotes myofibroblastic activation of hepatic stellate cells by distinct mechanisms selective for TGF-β receptor I versus II.Cell reports · 2022Article
- Polo-Like Kinase 2: From Principle to Practice.Frontiers in oncology · 2022Review
- The Role of the Hedgehog Pathway in Cholangiocarcinoma.Cancers · 2021Review
- Identification and assessment of PLK1/2/3/4 in lung adenocarcinoma and lung squamous cell carcinoma: Evidence from methylation profile.Journal of cellular and molecular medicine · 2021Article
- Review
- Targeted therapies for extrahepatic cholangiocarcinoma: preclinical and clinical development and prospects for the clinic.Expert opinion on investigational drugs · 2021Review
- CDK7 inhibitor THZ1 inhibits MCL1 synthesis and drives cholangiocarcinoma apoptosis in combination with BCL2/BCL-XL inhibitor ABT-263.Cell death & disease · 2019Article
- In vitro study of the Polo-like kinase 1 inhibitor volasertib in non-small-cell lung cancer reveals a role for the tumor suppressor p53.Molecular oncology · 2019Article
- Animal models of cholangiocarcinoma.Biochimica et biophysica acta. Molecular basis of disease · 2019Review
- Role of canonical Hedgehog signaling pathway in liver.International journal of biological sciences · 2018Review
- Emerging molecular therapeutic targets for cholangiocarcinoma.Journal of hepatology · 2017Review
- New Horizons for Precision Medicine in Biliary Tract Cancers.Cancer discovery · 2017Review
- Emerging concepts in biliary repair and fibrosis.American journal of physiology. Gastrointestinal and liver physiology · 2017Review
- Bcl-2 degradation is an additional pro-apoptotic effect of polo-like kinase inhibition in cholangiocarcinoma cells.World journal of gastroenterology · 2017Article
- MicroRNA-146a Induces Lineage-Negative Bone Marrow Cell Apoptosis and Senescence by Targeting Polo-Like Kinase 2 Expression.Arteriosclerosis, thrombosis, and vascular biology · 2017Article
- Autocrine and Paracrine Mechanisms Promoting Chemoresistance in Cholangiocarcinoma.International journal of molecular sciences · 2017Review
- Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA).Nature reviews. Gastroenterology & hepatology · 2016Article
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
Abstract
unlabelledCholangiocarcinoma (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.
conclusionPLK2 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.
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