title: Inhibition of adhesion, migration and of α5β1 integrin in the HCT-116 colorectal cancer cells treated with the ruthenium drug NAMI-A.
abstract: NAMI-A, imidazolium trans-imidazoledimethylsulfoxidetetrachlororuthenate, is a ruthenium-based drug characterised by the selective activity against tumour metastases. Previously we have shown the influence of the hepatic microenvironment to direct the arrest of the metastatic cells of colorectal cancer. Here we used the experimental model of HCT-116 colorectal cancer cells in vitro to explore whether the interference with α5β1 integrin may mechanistically explain the anti-metastatic effect of NAMI-A. NAMI-A inhibits two important steps of the tumour metastatic progression of colorectal cancer, i.e. the adhesion and migration of the tumour cells on the extracellular matrix proteins. The fibronectin receptor α5β1 integrin is likely involved in the anti-adhesive effects of NAMI-A on the HCT-116 colorectal cancer cells during their interaction with the extracellular matrix. Mechanistically, NAMI-A decreases the α5β1 integrin expression, and reduces FAK (Focal Adhesion Kinase) auto-phosphorylation on Tyr397, an important signalling event, involved in α5β1 integrin activation. These effects were validated by siRNA-induced knock down of the α5 integrin subunit and/or by the use of specific blocking mAbs against the active site of the integrin. Our results demonstrate the relevance of α5β1 integrin for colorectal cancer. We also show that the anti-metastatic effect of NAMI-A depends on the modulation of this integrin. Thus, our data on NAMI-A support the new concept that metal-based drugs can inhibit tumour metastases through targeting of integrins and of other proteins which mediate tumour progression-related cell functions such as adhesion and migration.
authors.affiliation: Callerio Foundation Onlus, Trieste, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pelillo
authors.affiliation: Callerio Foundation Onlus, Trieste, Italy.
authors.forename: Hilaria
authors.initials: H
authors.lastname: Mollica
authors.affiliation: Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, Germany.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Eble
authors.affiliation: Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, Germany.
authors.forename: Julius
authors.initials: J
authors.lastname: Grosche
authors.affiliation: Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Herzog
authors.affiliation: Dept of Engineering and Architecture, University of Trieste, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Codan
authors.affiliation: Callerio Foundation Onlus, Trieste, Italy; Dept of Life Sciences, University of Trieste, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Sava
authors.affiliation: Callerio Foundation Onlus, Trieste, Italy.
authors.forename: Alberta
authors.initials: A
authors.lastname: Bergamo
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry*; D017975:Ruthenium Compounds
chemical_list: D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D039081:Integrin alpha5beta1; D009942:Organometallic Compounds; D034741:RNA, Small Interfering; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); D012428:Ruthenium; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D004121:Dimethyl Sulfoxide
keywords: Colorectal cancer; Integrins; Metastasis; Ruthenium