Wnt5a suppresses epithelial ovarian cancer by promoting cellular senescence.

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.

[1]  Hosoon Choi,et al.  Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3–independent β-catenin degradation , 2003, The Journal of cell biology.

[2]  C. Oshima,et al.  Canonical and noncanonical Wnt pathway: a comparison among normal ovary, benign ovarian tumor and ovarian cancer. , 2009, Oncology reports.

[3]  Q. Tao,et al.  WNT5A antagonizes WNT/β-catenin signaling and is frequently silenced by promoter CpG methylation in esophageal squamous cell carcinoma , 2010, Cancer biology & therapy.

[4]  Hongli Yu,et al.  Wnt5a as a Predictor in Poor Clinical Outcome of Patients and a Mediator in Chemoresistance of Ovarian Cancer , 2010, International Journal of Gynecologic Cancer.

[5]  A. Bradley,et al.  Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. , 2003, Cancer cell.

[6]  Kathleen R. Cho,et al.  Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/beta-catenin and PI3K/Pten signaling pathways. , 2007, Cancer cell.

[7]  Q. Cai,et al.  Enhancer of Zeste Homolog 2 Promotes the Proliferation and Invasion of Epithelial Ovarian Cancer Cells , 2010, Molecular Cancer Research.

[8]  R. Moon.  Faculty Opinions recommendation of Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. , 2006 .

[9]  R. Nusse,et al.  Purified Wnt5a Protein Activates or Inhibits β-Catenin–TCF Signaling Depending on Receptor Context , 2006, PLoS biology.

[10]  Frédérick A. Mallette,et al.  Human fibroblasts require the Rb family of tumor suppressors, but not p53, for PML-induced senescence , 2004, Oncogene.

[11]  C Roskelley,et al.  A biomarker that identifies senescent human cells in culture and in aging skin in vivo. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Goberdhan P Dimri,et al.  Methods to detect biomarkers of cellular senescence: the senescence-associated beta-galactosidase assay. , 2007, Methods in molecular biology.

[13]  W F Bodmer,et al.  Target genes of beta-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[14]  H. Clevers,et al.  Wnt signalling in stem cells and cancer , 2005, Nature.

[15]  I. Shih,et al.  Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. , 2004, The American journal of pathology.

[16]  Rugang Zhang,et al.  Molecular Dissection of Formation of Senescence-Associated Heterochromatin Foci , 2007, Molecular and Cellular Biology.

[17]  Rosa Bernardi,et al.  Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies , 2007, Nature Reviews Molecular Cell Biology.

[18]  M. Collado.  Exploring a 'pro-senescence' approach for prostate cancer therapy by targeting PTEN. , 2010, Future oncology.

[19]  P. Adams.  Healing and hurting: molecular mechanisms, functions, and pathologies of cellular senescence. , 2009, Molecular cell.

[20]  Pier Paolo Pandolfi,et al.  PML regulates p53 acetylation and premature senescence induced by oncogenic Ras , 2000, Nature.

[21]  Ajamete Kaykas,et al.  WNT and β-catenin signalling: diseases and therapies , 2004, Nature Reviews Genetics.

[22]  D. Connolly,et al.  Xenograft and Transgenic Mouse Models of Epithelial Ovarian Cancer and Non‐Invasive Imaging Modalities to Monitor Ovarian Tumor Growth In Situ: Applications in Evaluating Novel Therapeutic Agents , 2009, Current protocols in pharmacology.

[23]  Pier Paolo Pandolfi,et al.  The Role of PML in Tumor Suppression , 2002, Cell.

[24]  T. Andersson,et al.  The Wnt-5a–Derived Hexapeptide Foxy-5 Inhibits Breast Cancer Metastasis In vivo by Targeting Cell Motility , 2008, Clinical Cancer Research.

[25]  H. Westphal,et al.  Abnormal structure and expression of the p53 gene in human ovarian carcinoma cell lines. , 1992, Cancer research.

[26]  A. Silver,et al.  The opposing roles of Wnt-5a in cancer , 2009, British Journal of Cancer.

[27]  D. Porteous,et al.  Identification and characterization of a homozygous deletion found in ovarian ascites by representational difference analysis. , 1999, Genome research.

[28]  R. Uzzo,et al.  Identification of novel target genes by an epigenetic reactivation screen of renal cancer. , 2006, Cancer research.

[29]  H Stein,et al.  Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. , 1984, Journal of immunology.

[30]  D. Peeper,et al.  The essence of senescence. , 2010, Genes & development.

[31]  E B Cox,et al.  Use of a monoclonal anti-estrogen receptor antibody in the immunohistochemical evaluation of human tumors. , 1986, Cancer research.

[32]  S. Lowe,et al.  Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas , 2011, Nature.

[33]  M. Birrer,et al.  Genomic analysis of epithelial ovarian cancer , 2008, Cell Research.

[34]  D. Peeper.  PICS-ure this: prosenescence therapy? , 2010, Cancer cell.

[35]  M. Katoh,et al.  WNT Signaling Pathway and Stem Cell Signaling Network , 2007, Clinical Cancer Research.

[36]  M. Lipinski,et al.  Definition of pRB- and p53-Dependent and -Independent Steps in HIRA/ASF1a-Mediated Formation of Senescence-Associated Heterochromatin Foci , 2007, Molecular and Cellular Biology.

[37]  Randall T Moon,et al.  WNT and beta-catenin signalling: diseases and therapies. , 2004, Nature reviews. Genetics.

[38]  W. Wong,et al.  A gene signature predictive for outcome in advanced ovarian cancer identifies a survival factor: microfibril-associated glycoprotein 2. , 2009, Cancer cell.

[39]  R. Ozols,et al.  Focus on epithelial ovarian cancer. , 2004, Cancer cell.

[40]  J. Herman,et al.  Alterations in DNA methylation: a fundamental aspect of neoplasia. , 1998, Advances in cancer research.

[41]  Robert A. Weinberg,et al.  Functional Inactivation of the Retinoblastoma Protein Requires Sequential Modification by at Least Two Distinct Cyclin-cdk Complexes , 1998, Molecular and Cellular Biology.

[42]  T. Jacks,et al.  Restoration of p53 function leads to tumour regression in vivo , 2007, Nature.

[43]  Rugang Zhang,et al.  Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells. , 2007, Molecular cell.

[44]  K. Brennand,et al.  Normal ovarian surface epithelial label-retaining cells exhibit stem/progenitor cell characteristics , 2008, Proceedings of the National Academy of Sciences.

[45]  Adrian A Canutescu,et al.  Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. , 2005, Developmental cell.

[46]  T. Pukrop,et al.  The complex pathways of Wnt 5a in cancer progression , 2008, Journal of Molecular Medicine.

[47]  Y. Minami,et al.  Cell/tissue-tropic Functions of Wnt5a Signaling in Normal and Cancer Cells , 2022 .

[48]  David F Jarrard,et al.  Therapy-induced senescence in cancer. , 2010, Journal of the National Cancer Institute.

[49]  S. Lowe,et al.  PML is induced by oncogenic ras and promotes premature senescence. , 2000, Genes & development.

[50]  J. Clohessy,et al.  A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. , 2010, The Journal of clinical investigation.

[51]  Ie-Ming Shih,et al.  The Origin and Pathogenesis of Epithelial Ovarian Cancer: A Proposed Unifying Theory , 2010, The American journal of surgical pathology.

[52]  Thomas Earnest,et al.  Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation. , 2002, Developmental cell.