3-Deazaneplanocin A May Directly Target Putative Cancer Stem Cells in Biliary Tract Cancer

Christian Mayr; Andrej Wagner; Angelika Stoecklinger; Martin Jakab; Romana Illig; Frieder Berr; Martin Pichler; Pietro Di Fazio; Matthias Ocker; Daniel Neureiter; Tobias Kiesslich

3-Deazaneplanocin A May Directly Target Putative Cancer Stem Cells in Biliary Tract Cancer

Anticancer Res. 2015 Sep;35(9):4697-705.

Authors

Affiliations

¹ Department of Internal Medicine I, Paracelsus Medical University, Salzburg, Austria Laboratory for Tumour Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria.
² Department of Internal Medicine I, Paracelsus Medical University, Salzburg, Austria.
³ Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
⁴ Laboratory for Functional and Molecular Membrane Physiology, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria.
⁵ Institute of Pathology, Paracelsus Medical University, Salzburg, Austria.
⁶ Laboratory for Tumour Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria.
⁷ Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
⁸ Department of Visceral, Thoracic and Vascular Surgery, Philipps University of Marburg, Marburg, Germany.
⁹ Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany.
¹⁰ Department of Internal Medicine I, Paracelsus Medical University, Salzburg, Austria Laboratory for Tumour Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria t.kiesslich@salk.at.

PMID: 26254359

Abstract

Background/aim: Polycomb repressive complex 2 (PRC2), an epigenetic master regulator, contributes to progression and development of biliary tract cancer (BTC). The present study investigated the effects of the PRC2 inhibitor 3-deazaneplanocin A (DZNep) on BTC cell lines.

Materials and methods: In vitro effects of DZNep treatment were analyzed for cell viability, gene expression and functional characteristics of cancer stem cell (CSC).

Results: DZNep treatment caused a cell line- and dose-dependent decrease in viability. In the EGI-1 cell line, a direct cytotoxic effect was accompanied by mRNA down-regulation of the PRC2 core components, cyclins as well as of CSC-related genes. Furthermore, DZNep affected putative CSCs by reduction of sphere formation and aldehyde dehydrogenase-1-positive cells. The stem cell characteristics of these subpopulations were verified by real-time polymerase chain reaction analysis.

Conclusion: Taken together, our results show that DZNep might be a promising pharmacological agent for future therapies regarding BTC.

Keywords: Biliary tract cancer; DZNep; EZH2; PRC2; anchorage-independent growth; cancer stem cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / pharmacology
Biliary Tract Neoplasms / genetics
Biliary Tract Neoplasms / pathology*
Biomarkers, Tumor / metabolism
Cell Death / drug effects
Cell Line, Tumor
Cell Survival / drug effects
Cyclins / genetics
Cyclins / metabolism
Dose-Response Relationship, Drug
Gene Expression Regulation, Neoplastic / drug effects
Humans
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology*
Polycomb Repressive Complex 2 / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism

Substances

Biomarkers, Tumor
Cyclins
RNA, Messenger
3-deazaneplanocin
Polycomb Repressive Complex 2
Adenosine