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The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). However, IRF5 activation status during the disease course and the effects of IRF5 inhibition after disease onset are unclear. Here, we show that SLE patients in both the active and remission phase have aberrant activation of IRF5 and interferon-stimulated genes. Partial inhibition of IRF5 is superior to full inhibition of type I interferon signaling in suppressing disease in a mouse model of SLE, possibly due to the function of IRF5 in oxidative phosphorylation. We further demonstrate that inhibition of IRF5 via conditional Irf5 deletion and a newly developed small-molecule inhibitor of IRF5 after disease onset suppresses disease progression and is effective for maintenance of remission in mice. These results suggest that IRF5 inhibition might overcome the limitations of current SLE therapies, thus promoting drug discovery research on IRF5 inhibitors. IRF5 is a potential target for therapy in systemic lupus erythematosus (SLE). Here the authors show using mouse SLE-like models that genetic or chemical inhibition of IRF5 after SLE onset could be more effective than, or an add on for, currently utilised type I interferon inhibition. [ABSTRACT FROM AUTHOR]

Purpose: Indisulam ( N-(-3-chloro-7-indolyl)-1,4-benzenedisulfonamide; E7070) is an experimental anticancer agent. Microarray analysis indicates that indisulam downregulates several genes involved in drug resistance, and this finding led us to test the effect of combining indisulam with other anticancer drugs. We investigated the antitumor effect and mechanism of synergism when indisulam was administered in combination with CPT-11. Methods: In vitro cytotoxic activity was examined using a cell counter kit, and the combination effect was determined by isobologram analysis. The level of topoisomerase IIα was measured by Western blotting. The in vivo antitumor effect was assessed in mice inoculated with human colorectal cancer SW620 cells. Results: Isobologram analysis indicated that a 24-h exposure to indisulam and SN-38, an active metabolite of CPT-11, had a synergistic effect in HCT116 and SW620 cells and an additive effect in HCT15 and WiDr cells. Prolongation of exposure to 48 h resulted in a synergistic effect in HCT15 and WiDr cells. Treatment with SN-38 alone increased the amount of intracellular topoisomerase IIα in all cell lines tested. Co-treatment with indisulam suppressed the SN-38-induced upregulation of topoisomerase IIα after 24 h of exposure in HCT116 and SW620 cells and after 48 h of exposure in HCT15 and WiDr cells. This apparent association between a synergistic effect and suppression of SN-38-mediated upregulation of topoisomerase IIα suggests that indisulam enhances SN-38 cytotoxicity by suppressing topoisomerase IIα upregulation to compensate for topoisomerase I inhibition by SN-38. Synergy was also observed in xenografted tumors and was accompanied by complete suppression of topoisomerase IIα upregulation induced by CPT-11 treatment. Conclusion: These observations prompted the clinical evaluation of indisulam and CPT-11 combination therapy. [ABSTRACT FROM AUTHOR]

ErbB2 and α6 integrin have been implicated in malignancy of breast cancer cells. Here we have determined the influence of α6β1 integrin on erbB2 signaling in anchorage-independent growth, using MDA-MB435 breast cancer cells. Firstly, we transfected the cells with erbB2 cDNA, and isolated cells with high or low levels of α6β1 integrin by cell sorting (α6H-ErbB and α6L-ErbB). We found that an erbB ligand, heregulin β1, enhanced growth activity of α6L-ErbB cells, but not α6H-ErbB cells. Secondly, we established cells expressing a β4 integrin deletion mutant (β4-Δcyt), which selectively inhibited α6β1 integrin expression and adhesion to laminin-1. Again, heregulin β1 enhanced the growth of erbB2 cDNA-transfected β4-Δcyt cells, but not mock cells. Western blot analysis revealed that heregulin β1 stimulated phosphorylation of Akt and its downstream molecules, GSK3β and p70S6kinase, and that the extent of phosphorylation was greater in ErbB2/β4-Δcyt cells than ErbB2/mock cells. Furthermore, we found that the erbB2 cytoplasmic domain was truncated in ErbB2/mock cells, which was independent of ligand stimulation and adhesion, and was suppressed by proteasome inhibitors. These results suggest that α6β1 integrin inhibits erbB2 signals by inducing proteasome-dependent proteolytic cleavage of the erbB2 cytoplasmic domain, and may thereby contribute to the regulation of tumor growth.Oncogene (2003) 22, 831–839. doi:10.1038/sj.onc.1206203 [ABSTRACT FROM AUTHOR]