Wnt5a Suppresses Epithelial Ovarian Cancer by Promoting Cellular Senescence

Abstract

Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy in the US. Thus, there is an urgent need to develop novel therapeutics for this disease. Cellular senescence is an important tumor suppression mechanism that has recently been suggested as a novel mechanism to target for developing cancer therapeutics. Wnt5a is a non-canonical Wnt ligand that plays a context-dependent role in human cancers. Here, we investigate the role of Wnt5a in regulating senescence of EOC cells. We demonstrate that Wnt5a is expressed at significantly lower levels in human EOC cell lines and in primary human EOCs (n = 130) compared with either normal ovarian surface epithelium (n = 31; p = 0.039) or fallopian tube epithelium (n = 28; p < 0.001). Notably, a lower level of Wnt5a expression correlates with tumor stage (p = 0.003) and predicts shorter overall survival in EOC patients (p = 0.003). Significantly, restoration of Wnt5a expression inhibits the proliferation of human EOC cells both in vitro and in vivo in an orthotopic EOC mouse model. Mechanistically, Wnt5a antagonizes canonical Wnt/β-catenin signaling and induces cellular senescence by activating the histone repressor A (HIRA)/promyelocytic leukemia (PML) senescence pathway. In summary, we show that loss of Wnt5a predicts poor outcome in EOC patients and Wnt5a suppresses the growth of EOC cells by triggering cellular senescence. We suggest that strategies to drive senescence in EOC cells by reconstituting Wnt5a signaling may offer an effective new strategy for EOC therapy.

Identification of ribonucleotide reductase M2 as a potential target for pro-senescence therapy in epithelial ovarian cancer

“…21,22 Indeed, recent studies from our lab and others have shown that induction of senescence pathways in tumor cells can cause tumor growth inhibition or regression. 19,20,37 The current study establishes that RRM2 is a potential target for developing pro-senescence therapy for EOC.…”

The Ubiquitin-like with PHD and Ring Finger Domains 1 (UHRF1)/DNA Methyltransferase 1 (DNMT1) Axis Is a Primary Regulator of Cell Senescence

“…5B), implying their transcriptional regulation by DNA methylation. Among the six tested genes, we focused on WNT5A because of its previously reported potential link to senescence (20). As expected, the WNT5A protein level was dose-dependently induced by blocking DNA methylation using 5-AzC (Fig.…”

Dysregulation of WNT5A/ROR2 Signaling Characterizes the Progression of Barrett-Associated Esophageal Adenocarcinoma

“…Given that b-catenin signaling induces tumor progression, these observations justify the WNT5A-mediated tumor suppression, in which ROR2 appears to have an essential role as receptor (37,39,40). Indeed, in ovarian cancer, WNT5A-mediated inhibition of b-catenin transcriptional activity has been associated with inhibition of tumor progress via cellular senescence (41). Taking into consideration that the canonical WNT/b-catenin signaling is activated in esophageal adenocarcinoma cancer cells (24), we could attribute the suppression of OE33 cell proliferation by WNT5A to the inhibition of b-catenin transcriptional activity, as shown by WNT5A-mediated decrease in TOPflash activity and AXIN2 gene expression.…”