The anti-apoptotic PON2 protein is Wnt/β-catenin-regulated and correlates with radiotherapy resistance in OSCC patients.

Autor:	Krüger M; Department of Oral and Maxillofacial Surgery - Plastic Surgery, University Medical Center of The Johannes Gutenberg-University, 55131 Mainz, Germany., Amort J; Department of Pharmacology, University Medical Center of The JGU Mainz, 55131 Mainz, Germany., Wilgenbus P; Department of Pharmacology, University Medical Center of The JGU Mainz, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis, University Medical Center of The JGU Mainz, 55131 Mainz, Germany., Helmstädter JP; Department of Pharmacology, University Medical Center of The JGU Mainz, 55131 Mainz, Germany., Grechowa I; Department of Pharmacology, University Medical Center of The JGU Mainz, 55131 Mainz, Germany.; Division of Vascular Surgery, Department of Cardiothoracic and Vascular Surgery, University Medical Center of The Johannes Gutenberg-University, 55131 Mainz, Germany., Ebert J; Department of Pharmacology, University Medical Center of The JGU Mainz, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis, University Medical Center of The JGU Mainz, 55131 Mainz, Germany., Tenzer S; Institute for Immunology, University Medical Center of The Johannes Gutenberg-University, 55131 Mainz, Germany., Moergel M; Department of Oral and Maxillofacial Surgery - Plastic Surgery, University Medical Center of The Johannes Gutenberg-University, 55131 Mainz, Germany., Witte I; Department of Pharmacology, University Medical Center of The JGU Mainz, 55131 Mainz, Germany., Horke S; Department of Pharmacology, University Medical Center of The JGU Mainz, 55131 Mainz, Germany.; Center for Thrombosis and Hemostasis, University Medical Center of The JGU Mainz, 55131 Mainz, Germany.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2016 Aug 09; Vol. 7 (32), pp. 51082-51095.
DOI:	10.18632/oncotarget.9013
Abstrakt:	Aberrant Wnt signaling and control of anti-apoptotic mechanisms are pivotal features in different types of cancer to undergo cell death programs. The intracellular human enzyme Paraoxonase-2 (PON2) is known to have anti-apoptotic properties in leukemia and oral squamous cell cancer (OSCC) cells. However, the distinct regulating pathways are poorly understood. First, we present a so far unknown regulation of PON2 protein expression through the Wnt/GSK3β/β-catenin pathway in leukemia and OSCC cells. This was confirmed via in silico analysis, promoter reporter studies and treatment of multiple cell lines (K562, SCC-4, PCI-13) with different Wnt ligands/inhibitors in vitro. Ex vivo analysis of OSCC patients revealed a correlation between PON2 and β-catenin expression in tumor tissue. Higher PON2 expression in OSCC is associated with relapse independently of treatment (e.g. surgery/radio-/chemotherapy). These results emphasize the clinical impact of the newly described regulation of PON2 through Wnt/GSK3β/β-catenin. More importantly, the study revealed the fundamental finding of an overall Wnt/GSK3β/β-catenin dependent regulation of PON2 in different cancers, which was confirmed by systematic and multimethodological approaches. Thus, the herein presented mechanistic insight contributes to a better understanding of tumor specific escape from cell death strategies and suggests PON2 as a new potential biomarker for therapy resistance or as a prognostic tumor marker. Competing Interests: The authors declare no conflicts of interest.
Databáze:	MEDLINE
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