title: The new sulindac derivative IND 12 reverses Ras-induced cell transformation.
abstract: The nonsteroidal anti-inflammatory drug Sulindac has chemopreventive and antitumorigenic properties. Its metabolites induce apoptosis and inhibit signaling pathways critical for malignant transformation, including the Ras pathway. Here we show that the new Sulindac derivative IND 12 reverses the phenotype of Ras-transformed MDCK-f3 cells and restores an untransformed epithelioid morphology characterized by growth in monolayers with regular cell-cell adhesions. Moreover, IND 12 treatment induces the expression at membranes of the cell adhesion protein E-cadherin and increases the level of the E-cadherin-bound beta-catenin. As a consequence, IND 12-treated MDCK-f3 cells lose their invasion capacity and regain the ability to aggregate. In the presence of IND 12, MDCK-f3 cells show regenerated expression and activity ratios of the small GTPases Rac and Rho normally found in untransformed MDCK cells. Strikingly, IND 12 treatment decreases the levels of phosphorylated mitogen-activated protein kinases, which are downstream substrates of the Ras-regulated Raf/mitogen-activated protein kinase pathway, and the level of Ras-induced activation of gene expression. Our findings identify a novel drug with high potential in cancer therapy by targeting Ras-induced cell transformation.
authors.affiliation: Max-Planck-Institut für molekulare Physiologie, 44227 Dortmund, Germany.
authors.forename: Ioanna-Maria
authors.initials: IM
authors.lastname: Karaguni
authors.forename: Peter
authors.initials: P
authors.lastname: Herter
authors.forename: Philip
authors.initials: P
authors.lastname: Debruyne
authors.forename: Slava
authors.initials: S
authors.lastname: Chtarbova
authors.forename: Alice
authors.initials: A
authors.lastname: Kasprzynski
authors.forename: Ulrike
authors.initials: U
authors.lastname: Herbrand
authors.forename: M-Reza
authors.initials: MR
authors.lastname: Ahmadian
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Glüsenkamp
authors.forename: Günther
authors.initials: G
authors.lastname: Winde
authors.forename: Marc
authors.initials: M
authors.lastname: Mareel
authors.forename: Tarik
authors.initials: T
authors.lastname: Möröy
authors.forename: Oliver
authors.initials: O
authors.lastname: Müller
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D002449:Cell Aggregation / Q000187:drug effects; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D011905:Genes, ras / Q000187:drug effects* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology*; D015534:Trans-Activators; D051176:beta Catenin
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D015820:Cadherins; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D015534:Trans-Activators; D051176:beta Catenin; C452601:sulindac derivative IND 12; D013467:Sulindac; D020929:Mitogen-Activated Protein Kinase Kinases