title: Wild-type p53 attenuates cancer cell motility by inducing growth differentiation factor-15 expression.
abstract: A major function of the p53 tumor suppressor is the regulation of the cell cycle and apoptosis. In addition to its well-documented functions in malignant cancer cells, p53 can also regulate cell migration and invasion, which contribute to metastasis. Growth differentiation factor-15 (GDF-15), a member of the TGF-β superfamily, has been shown to be a downstream target of p53 and is associated with diverse human diseases and cancer progression. In this study, we examined the potential role of GDF-15 in p53-regulated cancer cell motility. We show that overexpression of wild-type p53 in two highly invasive p53-null human cancer cell lines, SKOV3 and PC3, attenuated cell migration and the movement through Matrigel. Using wild-type p53 and DNA-binding-deficient p53 mutants, we found that the transcriptional activity of p53 is required in the induction of GDF-15 expression. Cell movement through uncoated and Matrigel-coated transwell decreased in response to treatment with recombinant GDF-15, whereas the cell proliferation was not affected by GDF-15 treatment. Moreover, the induction of GDF-15 expression and secretion by p53 and the reduction in cell movement through Matrigel were diminished by treatment with GDF-15 small interfering RNA. This study demonstrates a mechanism by which p53 attenuates cancer cell motility through GDF-15 expression. In addition, our results indicate that GDF-15 mediates the functions of p53 by autocrine/paracrine action.
authors.affiliation: Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia, 4490 Oak Street, Vancouver, British Columbia, Canada, V6H 3V5.
authors.forename: Jung-Chien
authors.initials: JC
authors.lastname: Cheng
authors.forename: Hsun-Ming
authors.initials: HM
authors.lastname: Chang
authors.forename: Peter C K
authors.initials: PC
authors.lastname: Leung
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53