title: Wnt5a suppresses epithelial ovarian cancer by promoting cellular senescence.
abstract: Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy in the United States. 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 noncanonical 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 show 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/promyelocytic leukemia 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.
authors.affiliation: Women's Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Bitler
authors.forename: Jasmine P
authors.initials: JP
authors.lastname: Nicodemus
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Cai
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Xiang
authors.initials: X
authors.lastname: Hua
authors.forename: Tianyu
authors.initials: T
authors.lastname: Li
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Paul
authors.initials: P
authors.lastname: Cairns
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics*; D005187:Fallopian Tubes / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009367:Neoplasm Staging; D009368:Neoplasm Transplantation; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism; D000071818:Wnt-5a Protein
chemical_list: D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein