Abstract
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.
Highlights
While cardiovascular diseases cause most mortalities in western societies at this time, cancer develops into a constantly increasing disease due to its age relatedness, leading to an expected rate of almost 1.7 Mio newly diagnosed cancer cases just in the U.S in 2015 [1]. in recent years, several new therapeutics have been developed to treat cancer, there is an increasing need to identify underlying mechanisms for the development of patient-tailored approaches
In case of Wnt stimulation, the inactivation of Glycogen-synthase kinase 3β (GSK-3β) causes a relief of the β-cat-destabilizing phosphorylation, allowing ß-cat to migrate into the nucleus for activation of transcription factors of the T-cell factor (Tcf)/lymphocyteenhancer-binding factor (Lef) family and adaption of gene expression [5]
Wnt signaling via the canonical and non-canonical pathway was identified to regulate hematopoietic ontogeny in fetal and adult hematopoiesis: Overexpression of Wnt proteins and defective GSK-3β were found to be associated with pre-B-cell leukemia and chronic myeloid leukemia (CML) respectively, while in acute myeloid leukemia (AML) overexpression of β-cat is associated with a poor prognosis [7], [8], [9], [10]
Summary
While cardiovascular diseases cause most mortalities in western societies at this time, cancer develops into a constantly increasing disease due to its age relatedness, leading to an expected rate of almost 1.7 Mio newly diagnosed cancer cases just in the U.S in 2015 [1]. in recent years, several new therapeutics have been developed to treat (or even cure) cancer, there is an increasing need to identify underlying mechanisms for the development of patient-tailored approaches. Padhi et al reported of a correlation between β-cat expression and poor prognosis in head and neck cancer [12] in vivo This is supported by the very recent finding that inactivation of several Wnt inhibitors through methylation is frequently found in oral cancer, correlating with a shorter survival [13]. Current and upcoming research has to gain more detailed insight in Wnt signaling to identify possible therapeutic targets by pharmacological agents or biologicals This hypothesis is strengthened by the remarkable finding that treatment of OSCC cell lines with anti-Wnt-1 antibodies diminished proliferation and induced apoptosis by blockade of the canonical pathway [16], [17]. These findings prompted us to analyze the in vivo PON2 expression in oral cancer and its role in patient’ irradiation resistance in a clinical setting
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