The anti-apoptotic PON2 protein is Wnt/β-catenin-regulated and correlates with radiotherapy resistance in OSCC patients.
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.
Department of Oral and Maxillofacial Surgery - Plastic Surgery, University Medical Center of The Johannes Gutenberg-University, 55131 Mainz, Germany.
Maximilian
M
Krüger
Department of Pharmacology, University Medical Center of The JGU Mainz, 55131 Mainz, Germany.
Julianna
J
Amort
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.
Petra
P
Wilgenbus
Department of Pharmacology, University Medical Center of The JGU Mainz, 55131 Mainz, Germany.
Johanna P
JP
Helmstädter
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.
Irina
I
Grechowa
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.
Julia
J
Ebert
Institute for Immunology, University Medical Center of The Johannes Gutenberg-University, 55131 Mainz, Germany.
Stefan
S
Tenzer
Department of Oral and Maxillofacial Surgery - Plastic Surgery, University Medical Center of The Johannes Gutenberg-University, 55131 Mainz, Germany.
Maximilian
M
Moergel
Department of Pharmacology, University Medical Center of The JGU Mainz, 55131 Mainz, Germany.
Ines
I
Witte
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.
Sven
S
Horke
D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D043303:Aryldialkylphosphatase / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000532:radiotherapy; D049109:Cell Proliferation / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020014:K562 Cells; D009062:Mouth Neoplasms / Q000235:genetics* / Q000532:radiotherapy; D011836:Radiation Tolerance / Q000235:genetics*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*
D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D043303:Aryldialkylphosphatase; C468411:PON2 protein, human
Wnt / beta-catenin; leukemia; oral squamous cancer cell; paraoxonase-2; tumor