DACT3-DVL1 Interaction-Mediated Canonical WNT Signaling Regulates Non-Small Cell Lung Cancer Progression and Cisplatin Resistance

Disheveled binding antagonist of β-catenin 3 (DACT3) is a negative regulator of canonical Wnt signaling. Dysregulation of disheveled 1 (DVL1) plays a role in malignant progression. However, the mechanism by which DVL1 transmits signals in the canonical Wnt pathway and the possible association between DVL1 and DACT3 remain unknown in non-small cell lung Cancer (NSCLC). Immunohistochemical evaluation of DACT3 and DVL1 expressions in resected NSCLC samples was performed. The biological behavior of NSCLC cells and the effect of transfection of DACT3/DVL1 cDNA and siRNA-DACT3 into NSCLC cells upon activation of canonical Wnt signaling were examined, using Western blot, luciferase activity assay, immunofluorescence, and co-immunoprecipitation. Reduced expression of DACT3 in NSCLC tissues showed a correlation with lymphatic metastasis and a poor prognosis in patients (p < 0.05). Additionally, a negative correlation was observed between the expression of DACT3 and that of DVL1. DACT3 inhibited the malignant phenotypes (invasion, proliferation, migration, tumorigenesis, and chemoresistance to cisplatin) of NSCLC cells induced by DVL1 through the Wnt/β-catenin pathway. DACT3-DVL1 interaction inhibited the phosphorylation of glycogen synthase kinase-3β (GSK-3β) at serine 9 and β-catenin at serine 675. Consequently, β-catenin nuclear translocation was reduced, leading to the inactivation of β-catenin-mediated transcription and downregulating the expressions of the protein factors related to cell malignancy. Our study confirms that the interaction between DVL1 and DACT3 inhibits the DVL1-induced activation of canonical Wnt signaling for inhibiting the NSCLC progression and cisplatin resistance.

WNT/β‐catenin signaling; cisplatin resistance; disheveled 1; disheveled binding antagonist of β‐catenin 3; malignant phenotype; non‐small cell lung cancer.