title: Inositol induces mesenchymal-epithelial reversion in breast cancer cells through cytoskeleton rearrangement.
abstract: Inositol displays multi-targeted effects on many biochemical pathways involved in epithelial-mesenchymal transition (EMT). As Akt activation is inhibited by inositol, we investigated if such effect could hamper EMT in MDA-MB-231 breast cancer cells. In cancer cells treated with pharmacological doses of inositol E-cadherin was increased, β-catenin was redistributed behind cell membrane, and metalloproteinase-9 was significantly reduced, while motility and invading capacity were severely inhibited. Those changes were associated with a significant down-regulation of PI3K/Akt activity, leading to a decrease in downstream signaling effectors: NF-kB, COX-2, and SNAI1. Inositol-mediated inhibition of PS1 leads to lowered Notch 1 release, thus contributing in decreasing SNAI1 levels. Overall, these data indicated that inositol inhibits the principal molecular pathway supporting EMT. Similar results were obtained in ZR-75, a highly metastatic breast cancer line. These findings are coupled with significant changes on cytoskeleton. Inositol slowed-down vimentin expression in cells placed behind the wound-healing edge and stabilized cortical F-actin. Moreover, lamellipodia and filopodia, two specific membrane extensions enabling cell migration and invasiveness, were no longer detectable after inositol addiction. Additionally, fascin and cofilin, two mandatory required components for F-actin assembling within cell protrusions, were highly reduced. These data suggest that inositol may induce an EMT reversion in breast cancer cells, suppressing motility and invasiveness through cytoskeleton modifications.
authors.affiliation: Department of Clinical and Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome, Italy; Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Via A. Scarpa 14, 00161 Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Dinicola
authors.affiliation: Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Via A. Scarpa 14, 00161 Rome, Italy; Department of Experimental Medicine, Sapienza University of Rome, Systems Biology Group Lab, viale Regina Elena 324, 00161 Rome, Italy.
authors.forename: Gianmarco
authors.initials: G
authors.lastname: Fabrizi
authors.affiliation: Department of Clinical and Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome, Italy; Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Via A. Scarpa 14, 00161 Rome, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Masiello
authors.affiliation: Department of Clinical and Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome, Italy; Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Via A. Scarpa 14, 00161 Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Proietti
authors.affiliation: Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Via A. Scarpa 14, 00161 Rome, Italy; Department of Experimental Medicine, Sapienza University of Rome, Systems Biology Group Lab, viale Regina Elena 324, 00161 Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Palombo
authors.affiliation: Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Via A. Scarpa 14, 00161 Rome, Italy; Department of Experimental Medicine, Sapienza University of Rome, Systems Biology Group Lab, viale Regina Elena 324, 00161 Rome, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Minini
authors.affiliation: Department of Zoology, College of Science, King Saud University, PO Box 2455, 11451 Riyadh, Saudi Arabia.
authors.forename: Abdel Halim
authors.initials: AH
authors.lastname: Harrath
authors.affiliation: Department of Zoology, College of Science, King Saud University, PO Box 2455, 11451 Riyadh, Saudi Arabia.
authors.forename: Saleh H
authors.initials: SH
authors.lastname: Alwasel
authors.affiliation: Department of Experimental Medicine - Histology and Embryology Lab., Second University of Naples, Via Luciano Armanni 5, 80138 Naples, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ricci
authors.affiliation: Department of Anatomy, Histology, Forensic Medicine and Orthopedics - Section of Histology and Medical Embryology, Sapienza University of Rome, Via A. Scarpa 14/16, 00161 Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Catizone
authors.affiliation: Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Via A. Scarpa 14, 00161 Rome, Italy; Azienda Policlinico Umberto I, viale del Policlinico 155, 00161 Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cucina
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Systems Biology Group Lab, viale Regina Elena 324, 00161 Rome, Italy. Electronic address: Mariano.bizzarri@uniroma1.it.
authors.forename: Mariano
authors.initials: M
authors.lastname: Bizzarri
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007294:Inositol / Q000494:pharmacology*; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology*; D008840:Microfilament Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D053764:Presenilin-1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D015820:Cadherins; D002352:Carrier Proteins; C502658:FSCN1 protein, human; D008840:Microfilament Proteins; D016328:NF-kappa B; D053764:Presenilin-1; D014746:Vimentin; D051176:beta Catenin; D007294:Inositol; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D053829:Amyloid Precursor Protein Secretases
keywords: Cytoskeleton; EMT; Inositol; Invasion; MET; Motility