Decreased Plakophilin-1 Expression Promotes Increased Motility in Head and Neck Squamous Cell Carcinoma Cells

Abstract

Desmosomes are prominent cell-cell adhesive junctions found in a variety of epithelial tissues, including the oral epithelium. The transmembrane core of the desmosome is composed of the desmosomal cadherins that interact extracellularly to mediate cell-cell adhesion. The cytoplasmic domain of desmosomal cadherins interact with plaque proteins that in turn interact with the keratin intermediate filament cytoskeleton. Plakophilin 1 is a major desmosomal plaque component that functions to recruit intermediate filaments to sites of cell-cell contact via interactions with desmoplakin. Decreased assembly of desmosomes has been reported in several epithelial cancers. We examined plakophilin-1 expression in an esophageal squamous cell carcinoma tissue microarray and found that plakophilin-1 expression inversely correlates with tumor grade. In addition, we sought to investigate the effect of plakophilin-1 expression on desmosome assembly and cell motility in oral squamous cell carcinoma cell lines. Cell lines expressing altered levels of plakophilin-1 were generated and the ability of these cells to recruit desmoplakin to sites of cell-cell contact was examined. Our results show that decreased expression of plakophilin-1 results in decreased desmosome assembly and increased cell motility and invasion. These data lead us to propose that loss of plakophilin-1 expression during head and neck squamous cell carcinoma (HNSCC) progression may contribute to an invasive phenotype.

Slug (SNAI2) expression in oral SCC cells results in altered cell-cell adhesion and increased motility

“…In addition, we have previously shown parental UM-SCC-38 cells are relatively immobile in culture. 13 We retrovirally expressed human Slug in UM-SCC-38 cells to generate a population of UM-SCC-38 cells expressing Slug. UM-SCC-38/slug cells display a distinct change in morphology compared to UM-SCC-38/neo cells infected with virus conferring G418 resistance (Fig.…”

Plakophilins in Desmosomal Adhesion and Signaling

“…However, the results of these studies are contradictory with up-regulation, down-regulation, or maintenance of desmosome components being reported. While the expression of PKPs1 -3 was increased in certain cancers of various origin (Furukawa et al, 2005;Cheung et al, 2007;Demirag et al, 2012;Takahashi et al, 2012), the loss or reduction of PKPs1 -3 was observed in the development and/or progression of the same or other cancers (Sobolik-Delmaire et al, 2007;Narayana et al, 2010;Demirag et al, 2011;Takahashi et al, 2012). Both conditions were correlated with advanced tumor grade, increased metastasis and/or poor prognosis.…”

Palmitoylation of plakophilin is required for desmosome assembly

“…A431D and A431DE cells were described previously (Lewis et al, 1997;Wahl, 2005). Generation of retroviral particles and retroviral infection has been described previously (Roberts et al, 2011;Sobolik-Delmaire et al, 2007). Retrovirally infected cell populations were routinely grown in DMEM containing 500 mg/ml G418 (Mediatech, Herndon, VA).…”

“…Antibodies against desmoplakin (20B6), desmoglein-2 (6D8), E-cadherin (4A2) and desmocollin-2/3 (7G6) were as described previously (Bazzi et al, 2006;Nieman et al, 1999;Sobolik-Delmaire et al, 2007;Wahl et al, 1996). Rabbit anti-desmoplakin (NW6) was a kind gift of Kathleen Green (Northwestern University, Chicago, IL).…”