The anti-apoptotic PON2 protein is Wnt/β-catenin-regulated and correlates with radiotherapy resistance in OSCC patients
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Maximilian Krüger1,*, Julianna Amort2,*, Petra Wilgenbus2,3, Johanna P. Helmstädter2, Irina Grechowa2,4, Julia Ebert2,3, Stefan Tenzer5, Maximilian Moergel1, Ines Witte2,#, Sven Horke2,3,#
1Department of Oral and Maxillofacial Surgery – Plastic Surgery, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany
2Department of Pharmacology, University Medical Center of the JGU Mainz, 55131 Mainz, Germany
3Center for Thrombosis and Hemostasis, University Medical Center of the JGU Mainz, 55131 Mainz, Germany
4Division of Vascular Surgery, Department of Cardiothoracic and Vascular Surgery, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany
5Institute for Immunology, University Medical Center of the Johannes Gutenberg-University, 55131 Mainz, Germany
*These individuals share first authorship
#These individuals share last authorship
Ines Witte, email: [email protected]
Keywords: paraoxonase-2, Wnt / beta-catenin, leukemia, oral squamous cancer cell, tumor
Received: March 16, 2016 Accepted: April 07, 2016 Published: April 26, 2016
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.
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