The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells
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Christian Mayr1,2, Andrej Wagner1, Magdalena Loeffelberger2, Daniela Bruckner3, Martin Jakab4, Frieder Berr2, Pietro Di Fazio5, Matthias Ocker6,7,8, Daniel Neureiter9, Martin Pichler10 and Tobias Kiesslich1,2
1 Department of Internal Medicine I, Salzburger Landeskliniken – SALK, Paracelsus Medical University, Salzburg, Austria
2 Laboratory for Tumor Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria
3 Research Program for Experimental Ophthalmology and Glaucoma Research, University Clinic of Ophthalmology and Optometry, Salzburger Landeskliniken – SALK, Paracelsus Medical University, Salzburg, Austria
4 Laboratory of Functional and Molecular Membrane Physiology, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria
5 Department of Visceral, Thoracic and Vascular Surgery, Philipps-University Marburg, Marburg, Germany
6 Institute for Surgical Research, Philipps-University Marburg, Marburg, Germany
7 Present address: Experimental Medicine Oncology, Bayer Pharma AG, Berlin, Germany
8 Present address: Department of Gastroenterology, Campus Benjamin Franklin, Charité University Medicine, Berlin, Germany
9 Institute of Pathology, Salzburger Landeskliniken – SALK, Paracelsus Medical University, Salzburg, Austria
10 Division of Oncology, Department of Internal Medicine, Medical University of Graz (MUG), Graz, Austria
Christian Mayr, email:
Keywords: biliary tract cancer, PRC1, PTC-209, cell cycle arrest, BMI1
Received: June 08, 2015 Accepted: November 14, 2015 Published: November 24, 2015
BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and is up-regulated in biliary tract cancer (BTC), contributing to aggressive clinical features. In this study we investigated the cytotoxic effects of PTC-209, a recently developed inhibitor of BMI1, in BTC cells. PTC-209 reduced overall viability in BTC cell lines in a dose-dependent fashion (0.04 - 20 µM). Treatment with PTC-209 led to slightly enhanced caspase activity and stop of cell proliferation. Cell cycle analysis revealed that PTC-209 caused cell cycle arrest at the G1/S checkpoint. A comprehensive investigation of expression changes of cell cycle-related genes showed that PTC-209 caused significant down-regulation of cell cycle-promoting genes as well as of genes that contribute to DNA synthesis initiation and DNA repair, respectively. This was accompanied by significantly elevated mRNA levels of cell cycle inhibitors. In addition, PTC-209 reduced sphere formation and, in a cell line-dependent manner, aldehyde dehydrogease-1 positive cells. We conclude that PTC-209 might be a promising drug for future in vitro and in vivo studies in BTC.
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