PT - JOURNAL ARTICLE AU - Giulia Benedetti AU - Michiel Fokkelman AU - Kuan Yan AU - Lisa Fredriksson AU - Bram Herpers AU - John Meerman AU - Bob van de Water AU - Marjo de Graauw TI - The Nuclear Factor <em>κ</em>B Family Member RelB Facilitates Apoptosis of Renal Epithelial Cells Caused by Cisplatin/Tumor Necrosis Factor <em>α</em> Synergy by Suppressing an Epithelial to Mesenchymal Transition–Like Phenotypic Switch AID - 10.1124/mol.112.084053 DP - 2013 Jul 01 TA - Molecular Pharmacology PG - 128--138 VI - 84 IP - 1 4099 - http://molpharm.aspetjournals.org/content/84/1/128.short 4100 - http://molpharm.aspetjournals.org/content/84/1/128.full SO - Mol Pharmacol2013 Jul 01; 84 AB - Cis-diamminedichloroplatinum(II) (cisplatin)–induced renal proximal tubular apoptosis is known to be preceded by actin cytoskeleton reorganization, in conjunction with disruption of cell-matrix and cell-cell adhesion. In the present study, we show that the proinflammatory cytokine tumor necrosis factor α (TNF-α) aggravated these cisplatin-induced F-actin and cell adhesion changes, which was associated with enhanced cisplatin-induced apoptosis of immortalized proximal tubular epithelial cells. TNF-α–induced RelB expression and lentiviral small hairpin RNA (shRNA)-mediated knockdown of RelB, but not other nuclear factor κB members, abrogated the synergistic apoptosis observed with cisplatin/TNF-α treatment to the level of cisplatin-induced apoptosis. This protective effect was associated with increased stress fiber formation, cell-matrix, and cell-cell adhesion in the shRNARelB (shRelB) cells during cisplatin/TNF-α treatment, mimicking an epithelial-to-mesenchymal phenotypic switch. Indeed, gene array analysis revealed that knockdown of RelB was associated with upregulation of several actin regulatory genes, including Snai2 and the Rho GTPase proteins Rhophilin and Rho guanine nucleotide exchange factor 3 (ARHGEF3). Pharmacological inhibition of Rho kinase signaling re-established the synergistic apoptosis induced by combined cisplatin/TNF-α treatment of shRelB cells. In conclusion, our study shows for the first time that RelB is required for the cisplatin/TNF-α–induced cytoskeletal reorganization and apoptosis in renal cells by controlling a Rho kinase–dependent signaling network.