title: Epithelial morphological reversion drives Profilin-1-induced elevation of p27(kip1) in mesenchymal triple-negative human breast cancer cells through AMP-activated protein kinase activation.
abstract: Profilin-1 (Pfn1) is an important regulator of actin polymerization that is downregulated in human breast cancer. Previous studies have shown Pfn1 has a tumor-suppressive effect on mesenchymal-like triple-negative breast cancer cells, and Pfn1-induced growth suppression is partly mediated by upregulation of cell-cycle inhibitor p27(kip1) (p27). In this study, we demonstrate that Pfn1 overexpression leads to accumulation of p27 through promoting AMPK activation and AMPK-dependent phosphorylation of p27 on T198 residue, a post-translational modification that leads to increased protein stabilization of p27. This pathway is mediated by Pfn1-induced epithelial morphological reversion of mesenchymal breast cancer through cadherin-mediated restoration of adherens junctions. These findings not only elucidate a potential mechanism of how Pfn1 may inhibit proliferation of mesenchymal breast cancer cells, but also highlight a novel pathway of cadherin-mediated p27 induction and therefore cell-cycle control in cells.
authors.affiliation: a Department of Bioengineering ; University of Pittsburgh ; Pittsburgh PA.
authors.forename: Chang
authors.initials: C
authors.lastname: Jiang
authors.affiliation: a Department of Bioengineering ; University of Pittsburgh ; Pittsburgh PA.
authors.forename: William
authors.initials: W
authors.lastname: Veon
authors.affiliation: b Department of Medicine ; Renal Electrolyte Division; University of Pittsburgh ; Pittsburgh PA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: b Department of Medicine ; Renal Electrolyte Division; University of Pittsburgh ; Pittsburgh PA.|c Department of Cell Biology ; University of Pittsburgh ; Pittsburgh PA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hallows
authors.affiliation: a Department of Bioengineering ; University of Pittsburgh ; Pittsburgh PA.|d Magee Women's Research Institute; University of Pittsburgh ; Pittsburgh PA.|e Department of Pathology ; University of Pittsburgh ; PA.
authors.forename: Partha
authors.initials: P
authors.lastname: Roy
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051304:Profilins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055550:Protein Stability; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: C495738:PFN1 protein, human; D051304:Profilins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Breast Cancer; Profilin-1; R-cadherin; p27kip1