title: Rosiglitazone and AS601245 decrease cell adhesion and migration through modulation of specific gene expression in human colon cancer cells.
abstract: PPARs are nuclear receptors activated by ligands. Activation of PPARγ leads to a reduction of adhesion and motility in some cancer models. PPARγ transcriptional activity can be negatively regulated by JNK-mediated phosphorylation. We postulated that the use of agents able to inhibit JNK activity could increase the effectiveness of PPARγ ligands. We analysed the effects of rosiglitazone (PPARγ ligand) and AS601245 (a selective JNK inhibitor) alone or in association on adhesion and migration of CaCo-2, HT29, and SW480 human colon cancer cells and investigated, through microarray analysis, the genes involved in these processes. Cell adhesion and migration was strongly inhibited by rosiglitazone and AS601245. Combined treatment with the two compounds resulted in a greater reduction of the adhesion and migration capacity. Affymetrix analysis in CaCo-2 cells revealed that some genes which were highly modulated by the combined treatment could be involved in these biological responses. Rosiglitazone, AS601245 and combined treatment down-regulated the expression of fibrinogen chains in all three cell lines. Moreover, rosiglitazone, alone or in association with AS601245, caused a decrease in the fibrinogen release. ARHGEF7/β-PIX gene was highly down-regulated by combined treatment, and western blot analysis revealed that β-PIX protein is down-modulated in CaCo-2, HT29 and SW480 cells, also. Transfection of cells with β-PIX gene completely abrogated the inhibitory effect on cell migration, determined by rosiglitazone, AS601245 and combined treatment. Results demonstrated that β-PIX protein is involved in the inhibition of cell migration and sustaining the positive interaction between PPARγ ligands and anti-inflammatory agents in humans.
authors: MerckSerono Ivrea - RBM SpA, Istituto di Ricerche Biomediche A Marxer, Colleretto Giacosa, Turin, Italy.
authors: Angelo
authors: A
authors: Cerbone
authors: Cristina
authors: C
authors: Toaldo
authors: Rosalba
authors: R
authors: Minelli
authors: Eric
authors: E
authors: Ciamporcero
authors: Stefania
authors: S
authors: Pizzimenti
authors: Piergiorgio
authors: P
authors: Pettazzoni
authors: Guglielmo
authors: G
authors: Roma
authors: Mario Umberto
authors: MU
authors: Dianzani
authors: Chiara
authors: C
authors: Ullio
authors: Carlo
authors: C
authors: Ferretti
authors: Chiara
authors: C
authors: Dianzani
authors: Giuseppina
authors: G
authors: Barrera
mesh_terms: D000097:Acetonitriles / Q000494:pharmacology*; D052160:Benzothiazoles / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D005340:Fibrinogen / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: C489138:1,3-benzothiazol-2-yl(2-((2-(3-pyridinyl)ethyl)amino)-4-pyrimidinyl)acetonitrile; D000097:Acetonitriles; D052160:Benzothiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D005340:Fibrinogen