Plakoglobin (also known as? -catenin) is a member of the Armadillo family of proteins and a paralog of β -catenin. Plakoglobin is a component of both the adherens junctions and desmosomes, and therefore plays a vital role in the regulation of cell-cell adhesion. Similar to β -catenin, plakoglobin is capable of participating in cell signaling in addition to its role in cell-cell adhesion. In this context, β -catenin has a well-documented oncogenic potential as a component of the Wnt signaling pathway. In contrast, while some studies have suggested a tumor promoting activity of plakoglobin in a cell/malignancy specific context, it generally acts as a tumor/metastasis suppressor. How plakoglobin acts as a growth/metastasis inhibitory protein has remained, until recently, unclear. Recent evidence suggests that plakoglobin may suppress tumorigenesis and metastasis by multiple mechanisms, including the suppression of oncogenic signaling, interactions with various proteins involved in tumorigenesis and metastasis, and the regulation of the expression of genes involved in these processes. This review is primarily focused on various mechanisms by which plakoglobin may inhibit tumorigenesis and metastasis.

Aberrant expression of cadherins and catenins plays pivotal roles in ovarian cancer development and progression. Plakoglobin (PG, γ-catenin) is a paralog of β-catenin with dual adhesive and signaling functions. While β-catenin has known oncogenic function, PG generally acts as a tumor/metastasis suppressor. We recently showed that PG interacted with p53 and that its growth/metastasis inhibitory function may be mediated by this interaction. Very little is known about the role of PG in ovarian cancer. Here, we investigated the in vitro tumor/metastasis suppressor effects of PG in ovarian cancer cell lines with mutant p53 expression and different cadherin profiles. We showed that the N-cadherin expressing and E-cadherin and PG deficient ES-2 cells were highly migratory and invasive, whereas OV-90 cells that express E-cadherin, PG and very little/no N-cadherin were not. Exogenous expression of PG or E-cadherin or N-cadherin knockdown in ES-2 cells (ES-2-E-cad, ES-2-PG and ES-2-shN-cad) significantly reduced their migration and invasion. Also, PG expression or N-cadherin knockdown significantly decreased ES-2 cells growth. Furthermore, PG interacted with both cadherins and with wild type and mutant p53 in normal ovarian and ES-2-PG cell lines, respectively.

Plakoglobin (PG) is a paralog of β-catenin with similar adhesive, but contrasting signalling functions. Although β-catenin has well-known oncogenic function, PG generally acts as a tumor/metastasis suppressor by mechanisms that are just beginning to be deciphered. Previously, we showed that PG interacted with wild type (WT) and a number of mutant p53s, and that its tumor/metastasis suppressor activity may be mediated, at least partially, by this interaction. Here, carcinoma cell lines deficient in both p53 and PG (H1299), or expressing mutant p53 in the absence of PG (SCC9), were transfected with expression constructs encoding WT and different fragments and deletions of p53 and PG, individually or in pairs. Transfectants were characterized for their in vitro growth, migratory and invasive properties and for mapping the interacting domain of p53 and PG. We showed that when coexpressed, p53-WT and PG-WT cooperated to decrease growth, and acted synergistically to significantly reduce cell migration and invasion. The DNA-binding domain of p53 and C-terminal domain of PG mediated p53/PG interaction, and furthermore, the C-terminus of PG played a central role in the inhibition of invasion in association with p53.

Tumor suppressor/transcription factor p53 is mutated in over 50% of all cancers. Some mutant p53 proteins have not only lost tumor suppressor activities but they also gain oncogenic functions (GOF). One of the most frequently expressed GOF p53 mutants is Arg175His (p53R175H) with well‐documented roles in cancer development and progression. Plakoglobin is a cell adhesion and signaling protein and a paralog of β‐catenin. Unlike β‐catenin that has oncogenic function through its role in the Wnt pathway, plakoglobin generally acts as a tumor/metastasis suppressor. We have shown that plakoglobin interacted with wild type and a number of p53 mutants in various carcinoma cell lines. Plakoglobin and mutant p53 interacted with the promoter and regulated the expression of several p53 target genes. Furthermore, plakoglobin interactions with p53 mutants restored their tumor suppressor/metastasis activities in vitro. GOF p53 mutants induce accumulation and oncogenic activation of β‐catenin. Previously, we showed that one mechanism by which plakoglobin may suppress tumorigenesis is by sequestering β‐catenin's oncogenic activity. Here, we examined the effects of p53R175H expression on β‐catenin accumulation and transcriptional activation and their modifications by plakoglobin coexpression. We showed that p53R175H expression in plakoglobin null cells increased total and nuclear levels of β‐catenin and its transcriptional activity. Coexpression of plakoglobin in these cells promoted β‐catenin's proteasomal degradation, and decreased its nuclear levels and transactivation. Wnt/β‐catenin targets, c‐MYC and S100A4 were upregulated in p53R175H cells and were downregulated when plakoglobin was coexpressed. Plakoglobin‐p53R175H cells also showed significant reduction in their migration and invasion in vitro.

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