PCDH10 inhibits cell proliferation of multiple myeloma via the negative regulation of the Wnt/β-catenin/BCL-9 signaling pathway

Abstract

Abstract. The tumor suppressor protocadherin-10 (PCDH10) gene is important in cell proliferation, survival, apoptosis and migration. Inactivation of PCDH10 by promoter methylation is a frequent pathogenetic event in multiple myeloma (MM). The Wnt/β-catenin pathway is known to be involved in the cell growth of various types of cancer, including MM. However, the relationship between PCDH10 and Wnt signaling in MM remains unclear. In this study, we found that PCDH10 deficiency highly enhanced MM cell proliferation, Wnt signaling and the expression of BCL-9, an essential coactivator of Wnt transcriptional activity that is correlated with cell growth, survival and drug resistance. Restoration of PCDH10 suppressed nuclear localization of β-catenin, the activity of LEF/TCF, the expression of BCL-9 and AKT, whereas the expression of GSK3β was increased. The antagonistic effect of PCDH10 was associated with G1-phase blockage. Collectively, PCDH10 antagonized MM cell proliferation via the downregulation of Wnt/β-catenin/BCL-9 signaling, whereas PCDH10 repressed the expression of AKT to promote the expression of GSK3β and then to restrain the activation of β-catenin. Thus, the results offer a novel preclinical rationale in order to explore PCDH10 as an effective and selective therapeutic strategy to eradicate MM cells.

PCDH10 gene inhibits cell proliferation and induces cell apoptosis by inhibiting the PI3K/Akt signaling pathway in hepatocellular carcinoma cells

“…Phosphorylation of MDM2 mediates ubiquitination and degradation of p53, a well-known molecule with various biological functions (30,31). In our study, we demonstrated that PCDH10 inhibited HCC cell proliferation and increased cell apoptosis, and in view of the research on PCDH10 in other tumors (19,28), we put forward the hypothesis that PCDH10 may regulate the Akt signaling pathway in HCC. We detected the Akt signaling pathway and found that the protein levels of p-Akt, p-MDM2, Bcl-2 and cyclin D1 were decreased while p53, p-GSK3β, p21, Bax and caspase-3 were increased in cells transfected with PCDH10 when compared to the control groups.…”

“…It has been reported that PCDH10/OL-PC interacts with Nck-associated protein 1 (Nap1)/WAVE1 and that the PCDH10/Nap1/WAVE1 complex affects actin assembly and subsequently regulates cell migration (25,26). Recent studies demonstrated that PCDH10 is involved in some signaling pathways, including the nuclear factor-κB signaling pathway and the Wnt/β-catenin/BCL-9 signaling pathway (27,28). These results demonstrate that PCDH10 carries out the suppressive function via interference with the signaling pathways that are involved in malignancy.…”

“…PCDH10 plays an important role in cell-cell signal conduction, and previous studies have demonstrated that PCDH10 could regulate pathways relating to tumorigenesis and tumor progression (27,28). In this study, we observed a difference of phenotype in HCC cells after overexpression of PCDH10.…”

The Cadherin Superfamily in Neural Circuit Assembly

“…Together, the studies on Pcdh11 and Pcdh19 reveal a role for δ-Pcdhs in controlling neuronal differentiation. Moreover, evidence from non-neuronal systems suggests that this role involves links to Wnt signaling pathways, as both Pcdh10 and Pcdh17 have been shown to act as tumor suppressors by inhibiting β-catenin and Wnt signaling (Xu et al 2015b; Yin et al 2016). Additionally, several δ-Pcdhs interact with the Wnt receptor, Ryk (Berndt et al, 2011).…”

Epigenetic silencing of protocadherin 10 in colorectal cancer

“…Previous studies have demonstrated that PCDH10 is involved in several important biological pathways in different types of tumor cells. Although PCDH10 appears to lack the β-catenin binding cytoplasmic site present in classical cadherins (21), it may affect the Wnt/β-catenin signaling pathway (22,23). It was revealed that PCDH10 induced apoptosis by inhibiting the nuclear factor (NF)-κB pathway in myeloma cells (24), or by interacting with human brain expressed X-linked 1 in imatinib-induced K562 cell apoptosis (25), indicating the proapoptotic and drug-resistance reversal role of PCDH10.…”