title: Mutation or loss of p53 differentially modifies TGFβ action in ovarian cancer.
abstract: Ovarian cancer is the most lethal gynecological disease affecting women in the US. The Cancer Genome Atlas Network identified p53 mutations in 96% of high-grade serous ovarian carcinomas, demonstrating its critical role. Additionally, the Transforming Growth Factor Beta (TGFβ) pathway is dysfunctional in various malignancies, including ovarian cancer. This study investigated how expression of wild-type, mutant, or the absence of p53 alters ovarian cancer cell response to TGFβ signaling, as well as the response of the ovarian surface epithelium and the fallopian tube epithelium to TGFβ. Only ovarian cancer cells expressing wild-type p53 were growth inhibited by TGFβ, while ovarian cancer cells that were mutant or null p53 were not. TGFβ induced migration in p53 null SKOV3 cells, which was not observed in SKOV3 cells with stable expression of mutant p53 R273H. Knockdown of wild-type p53 in the OVCA 420 ovarian cancer cells enhanced cell migration in response to TGFβ. Increased protein expression of DKK1 and TMEPAI, two pro-invasive genes with enhanced expression in late stage metastatic ovarian cancer, was observed in p53 knockdown and null cells, while cells stably expressing mutant p53 demonstrated lower DKK1 and TMEPAI induction. Expression of mutant p53 or loss of p53 permit continued proliferation of ovarian cancer cell lines in the presence of TGFβ; however, cells expressing mutant p53 exhibit reduced migration and decreased protein levels of DKK1 and TMEPAI.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Eoghainín
authors.initials: E
authors.lastname: Ó hAinmhire
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Quartuccio
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Whay
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Roshan A
authors.initials: RA
authors.lastname: Ahmed
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Shelby M
authors.initials: SM
authors.lastname: King
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Burdette
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D019656:Loss of Heterozygosity; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010053:Ovary / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D014945:Wound Healing
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C412868:PMEPA1 protein, human; C495901:TP53 protein, human; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53