P63 and Tight Junctions Targeted for Therapy in Human Salivary Duct Adenocarcinoma Cells.

Salivary gland cancer is a rare heterogeneous group of neoplasms with complex histopathologic patterns, including carcinoma with squamous differentiation, for which surgery is the standard treatment. However, further research is essential for developing new therapies. Head and neck squamous cell carcinoma is positive for p63 and negative for the bicellular tight junction protein cingulin (CGN). p63 plays a key role in cancer progression such as cell proliferation, migration, apoptosis, and squamous differentiation. To understand the roles of p63 in salivary duct adenocarcinoma, we investigated the malignancy by using overexpression of deltaNp63 in p63-negative salivary duct adenocarcinoma cells PGC2E derived from parotid gland duct adenocarcinoma. By transfection with deltaNp63, the PGC2E cells exhibited increased nuclear p63 expression and reduced CGN levels at the membrane. Overexpression of deltaNp63 disrupted epithelial polarity and epithelial permeability barriers, promoted cell proliferation and migration, and enhanced cellular metabolism. Treatment with inhibitors of histone deacetylase and nuclear factor kappa B, and antibodies to tumor necrosis factor-α and tricellular tight junction protein lipolysis-stimulated lipoprotein receptor induced apoptosis in PGC2E cells. However, overexpression of deltaNp63 prevented the induced apoptosis. These findings suggest that p63 contributes to cancer malignancy and the complex phenotype, and it may be possible to develop a novel treatment via p63.