DRES-07. MODULATION OF INFLAMMATION PROFILES AND AHR SIGNALING IN HUMAN GLIOBLASTOMA MULTIFORME CELL LINES BY INDIRUBIN DERIVATIVES E804 AND 7BIO

Abstract

Glioblastoma Multiforme (GBM) is a highly invasive brain tumor that affects approximately 18,000 people annually in the US alone. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that binds endogenous, indole-derived ligands as well as many planar xenobiotics. In addition to regulating drug and xenobiotic metabolism, AHR signaling is involved in hematopoiesis, immune function, cell cycling, and inflammation. As new treatment options for GBM are developed, inflammation is emerging as a concern in the success of these new modalities. Indirubin and many of its derivatives bind AHR with different affinities based on their structure activity relationships (SAR). Depending on the SAR, AHR activation has a range of effects on cell physiology. We examined the effects of two indirubin derivatives: Indirubin-3’-(2,3 dihydroxypropyl)-oximether (E804) and 7-Bromoindirubin-3’-oxime (7BIO) on AHR activity and inflammation profiles in LN-18 and T98G human glioma cell lines. CYP1B1 gene expression, a marker for AHR activation, is induced in both cell lines, and most potently by E804. Using a commercial cancer-inflammation qPCR array, we showed that gene expression profiles indicative of pro-inflammation are highly suppressed by E804, with 7BIO having little effect. Of note, this suppression of pro-inflammatory gene expression occurred in LN-18 cells, but not T98G cells. IL6 protein secretion, an iconic inflammatory cytokine, was decreased by E804 as compared to the control at two time points and in both cell lines. Furthermore, in LN-18 cells, 7BIO reduced the expression of indoleamine dioxygenase (IDO1), a key enzyme for glioma survival. In contrast, however, IDO1 expression was induced in 7BIO-treated T98G cells. Moreover, expression of the regulatory transcription factor STAT3 was reduced by E804, but not by 7BIO in both cell lines. Thus, E804 is both an AHR ligand and inhibitor of STAT3, and may have potential in future treatments for GBM.