title: Mutant p53 promotes ovarian cancer cell adhesion to mesothelial cells via integrin β4 and Akt signals.
abstract: Missense mutations in the TP53 gene resulting in the accumulation of mutant proteins are extremely common in advanced ovarian cancer, which is characterised by peritoneal metastasis. Attachment of cancer cells to the peritoneal mesothelium is regarded as an initial, key step for the metastatic spread of ovarian cancer. In the present study, we investigated the possible role of a p53 mutant in the mesothelial adhesion of ovarian cancer cells. We found that OVCAR-3 cells with the R248 TP53 mutation (p53(R248)) were more adhesive to mesothelial Met5A cells than were A2780 cells expressing wild-type p53. In addition, ectopic expression of p53(R248) in p53-null SKOV-3 cells significantly increased adhesion to Met5A cells. Knockdown of mutant p53 significantly compromised p53(R248)-induced cell adhesion to Met5A cells. Microarray analysis revealed that several adhesion-related genes, including integrin β4, were markedly up-regulated, and certain signalling pathways, including PI3K/Akt, were activated in p53(R248) transfectants of SKOV-3 cells. Inhibition of integrin β4 and Akt signalling using blocking antibody and the inhibitor LY294002, respectively, significantly attenuated p53(R248)-mediated ovarian cancer-mesothelial adhesion. These data suggest that the p53(R248) mutant endows ovarian cancer cells with increased adhesiveness and that integrin β4 and Akt signalling are associated with the mutation-enhanced ovarian cancer-mesothelial cell adhesion.
authors.affiliation: Department of Life &Nanopharamceutical Science, Kyung Hee University, Seoul 130-701, South Korea.|Department of Oriental Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130-701, South Korea.
authors.forename: Jong-Gyu
authors.initials: JG
authors.lastname: Lee
authors.affiliation: Department of Life &Nanopharamceutical Science, Kyung Hee University, Seoul 130-701, South Korea.|Department of Oriental Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130-701, South Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Ahn
authors.affiliation: Department of Obstetrics and Gynecology, Cheil General Hospital and Women's Healthcare Center, Dankook University College of Medicine, Seoul 100-380, South Korea.
authors.forename: Tae
authors.initials: T
authors.lastname: Jin Kim
authors.affiliation: Laboratory of Molecular Oncology, Cheil General Hospital and Women's Healthcare Center, Dankook University College of Medicine, Seoul 100-380, South Korea.
authors.forename: Jae
authors.initials: J
authors.lastname: Ho Lee
authors.affiliation: Department of Life &Nanopharamceutical Science, Kyung Hee University, Seoul 130-701, South Korea.|Department of Oriental Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130-701, South Korea.
authors.forename: Jung-Hye
authors.initials: JH
authors.lastname: Choi
mesh_terms: D019943:Amino Acid Substitution; D002448:Cell Adhesion / Q000235:genetics; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D020125:Mutation, Missense; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C059834:ITGB4 protein, human; D039663:Integrin beta4; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt