title: PMA-induced reduction in invasiveness is associated with hyperphosphorylation of MARCKS and talin in invasive bladder cancer cells.
abstract: Protein kinase C (PKC) plays a critical role in signal transduction for a variety of cell activation processes. Enhanced PKC activity is often found in cancer cells that show marked invasive and/or metastatic potential. Thus, a specific PKC inhibitor may serve as a tool to reduce invasive or metastatic potential of cancer cells. We show here that phorbol 12-myristate 13-acetate (PMA), a PKC activator, also reduces invasiveness of EJ invasive transitional carcinoma cells. PMA-induced reduction in invasiveness was parallel with inhibition of cell motility. PMA neither induced E-cadherin expression nor augmented cell-matrix adhesion of EJ cells. PMA caused retraction of microspikes from the rim of the cells and consequently rounding of the cellular rim, and the disappearance of microfilaments from the cytoplasm. PMA at 10(-7) M, at which concentration the motility of EJ cells was completely inhibited, down-regulated PKC activity over 5 hr after transient translocation of PKC activity to the membrane fraction. At the same time, PMA induced hyperphosphorylation of MARCKS and talin. During the process of cell movement, actin-binding proteins are in a cycle of phosphorylation and dephosphorylation. Once this cycle is interrupted, cells can no longer maintain the dynamics of cytoskeletal structure. We suggest that retention of the hyperphosphorylated state of MARCKS and talin is responsible for the mechanism(s) by which PMA produces inhibitory activity against invasiveness of EJ cells.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029-6574, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: T
authors.initials: T
authors.lastname: Ito
authors.forename: V
authors.initials: V
authors.lastname: Hanson
authors.forename: G K
authors.initials: GK
authors.lastname: Schwartz
authors.forename: A A
authors.initials: AA
authors.lastname: Aderem
authors.forename: J F
authors.initials: JF
authors.lastname: Holland
authors.forename: T
authors.initials: T
authors.lastname: Tamaya
authors.forename: T
authors.initials: T
authors.lastname: Ohnuma
mesh_terms: D000199:Actins / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002462:Cell Membrane / Q000648:ultrastructure; D002465:Cell Movement / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D016608:Talin / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000473:pathology*; D016596:Vinculin / Q000378:metabolism
chemical_list: D000199:Actins; D015820:Cadherins; D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; D008565:Membrane Proteins; D011506:Proteins; D016608:Talin; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D016596:Vinculin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate