xav939 and Ovarian-Neoplasms

Canonical Wnt/ β-catenin pathway is one mechanism being activated in platinum-resistant epithelial ovarian cancer (EOC). Detecting potential targets for Wnt pathway modulation as a putative future therapeutic approach was the aim of this study.. Biological effects of different Wnt modulators (SB216763, XAV939 and triptolide) on the EOC cell lines A2780 and its platinum-resistant clone A2780cis were investigated via multiple functional tests. Immunohistochemistry (IHC) was carried out to compare the expression levels of Wnt marker proteins (β-catenin, snail/ slug, E-cadherin) in patient specimens and to correlate them with lifetime data.. We could show that activated Wnt signaling of the platinum-resistant EOC cell line A2780cis can be reversed by Wnt manipulators through SB216763 or XAV939. All Wnt manipulators tested consecutively decreased cell proliferation and cell viability. Apoptosis of A2780 and A2780cis was enhanced by triptolide in a dose-dependent manner, whereas cell migration was inhibited by SB216763 and triptolide. IHC analyses elucidated significantly different expression patterns for Wnt markers in the serous subtype. Herein, higher plasmatic snail/ slug expression is associated with improved progression-free (PFS) and overall survival (OS).. According to the described effects on EOC biology, all three Wnt manipulators seem to have the potential to augment the impact of a platinum-based chemotherapy in EOC. This is promising as a dominance of this pathway was confirmed in serous histology.

Topics: Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; beta Catenin; Cadherins; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Movement; Diterpenes; Drug Resistance, Neoplasm; Epoxy Compounds; Female; Heterocyclic Compounds, 3-Ring; Humans; Indoles; Maleimides; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Ovarian Neoplasms; Phenanthrenes; Wnt Signaling Pathway

Golgi phosphoprotein 3 (GOLPH3), a newly recognized oncogene, is associated with tumor growth, metastasis, and poor prognosis in several types of cancer. However, its biological role and underlying mechanism in epithelial ovarian cancer (EOC) remain poorly understood. Here, we found that GOLPH3 was overexpressed in EOC tissues and cell lines. This overexpression promoted the migration and invasion of EOC cells. Moreover, GOLPH3 upregulated the expression of epithelial-mesenchymal transition (EMT) markers, such as N-cadherin and Snail, and the Wnt/β-catenin-related genes cyclin-D1 and c-Myc, which were restored via silencing of GOLPH3 expression. Furthermore, the inhibitor and activator of the Wnt/β-catenin pathway, XAV939 and LiCl, enhanced or decreased, respectively, the effect of GOLPH3 on EMT, which further confirmed that GOLPH3 promoted EMT progression via activation of Wnt/β-catenin signaling. In addition, we found that EDD, the human hyperplastic discs gene, was consistent with GOLPH3 expression and also promoted the EMT process and activated Wnt/β-catenin signaling. These findings demonstrate that EDD might be a downstream factor of GOLPH3. Taken together, our findings demonstrate the existence of a GOLPH3-Wnt/β-catenin-EMT axis in EOC and provide a new therapeutic target to treat EOC.

Topics: Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 3-Ring; Humans; Membrane Proteins; Neoplasm Invasiveness; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Ubiquitin-Protein Ligases; Up-Regulation; Wnt Signaling Pathway