Indirubins decrease glioma invasion by blocking migratory phenotypes in both the tumor and stromal endothelial cell compartments.
ABSTRACT Invasion and proliferation in neoplasia require the cooperation of tumor cell and endothelial compartments. Glycogen synthase kinase-3 (GSK-3) is increasingly recognized as a major contributor to signaling pathways that modulate invasion and proliferation. Here we show that GSK-3 inhibitors of the indirubin family reduce invasion of glioma cells and glioma-initiating cell-enriched neurospheres both in vitro and in vivo, and we show that β-catenin signaling plays an important role in mediating these effects. Indirubins improved survival in glioma-bearing mice in which a substantial decrease in blood vessel density was seen in treated animals. In addition, indirubins blocked migration of endothelial cells, suggesting that anti-invasive glioma therapy with GSK-3 inhibitors in vivo not only inhibits invasion of tumor cells, but blocks migration of endothelial cells, which is also required for tumor angiogenesis. Overall, our findings suggest that indirubin inhibition of GSK-3 offers a novel treatment paradigm to target 2 of the most important interacting cellular compartments in heterotypic models of cancer.
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ABSTRACT: While metastasis is the chief cause of cancer mortality, there nonetheless remains a lack of anti-metastatic therapies that are clinically available. In this study, we present the indirubin derivative 6-bromo-indirubin-3'-oxime (6BIO) as a promising antimetastatic agent. 6BIO strongly reduced formation of lung metastasis in the well-established 4T1 mouse model of aggressive breast cancer. Several major hallmarks of the metastatic process were affected by subtoxic concentrations of 6BIO, which inhibited adhesion, migration and invasion of a variety of metastatic cell types in vitro. Mechanistic analyses focused on known targets of 6BIO, which were silenced by this compound. Unexpectedly, RNAi-mediated silencing of GSK3β and PDK1, both modulators of cellular metastasis targeted by 6BIO, were not found to affect invasive migration in this study. Instead, the Jak/STAT3 signaling pathway appeared to play a major role through modulation of its downstream migration regulators CTEN and MMP2. However, PDK1 and GSK3β contributed to the overall response to 6BIO, as silencing of all three pathways resulted in almost complete inhibition of migration, phenocopying the 6BIO response. Taken together, our findings illustrate the anti-metastatic activity of 6BIO based on its ability to simultaneously inhibit several kinase cascades involved in metastasis of cancer cells, supporting the concept of "polypharmacology" in developing drugs to attack metastasis, the most deadly aspect of cancer.Cancer Research 08/2013; · 9.28 Impact Factor
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ABSTRACT: The aryl hydrocarbon receptor (AHR) is highly expressed in multiple organs and tissues, and there is increasing evidence that the AHR plays an important role in cellular homeostasis and disease. The AHR is expressed in multiple tumor types, in cancer cell lines, and in tumors from animal models, and the function of the AHR has been determined by RNA interference (RNAi), overexpression and inhibition studies. With few exceptions, knockdown of the AHR resulted in decreased proliferation and/or invasion and migration of cancer cell lines and in vivo studies in mice overexpressing the constitutively-active AHR exhibited enhanced stomach and liver cancers, suggesting a pro-oncogenic role for the AHR. In contrast, loss of the AHR in transgenic mice that spontaneously develop colonic tumors and in carcinogen-induced liver tumors resulted in increased carcinogenesis, suggesting that the receptor may exhibit antitumorigenic activity prior to tumor formation. AHR ligands also either enhanced or inhibited tumorigenesis and these effects were highly tumor-specific, demonstrating that selective AHR modulators (SAhRMs) that exhibit agonist or antagonist activities represent an important new class of anticancer agents that can be directed against multiple tumors.Toxicological Sciences 06/2013; · 4.48 Impact Factor
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ABSTRACT: Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication in cancer, including by conveying tumor-promoting microRNAs between cells, but their regulation is poorly understood. In this study, we report the findings of a comparative microRNA profiling and functional analysis in human glioblastoma (GBM) that identifies miR-1 as an orchestrator of EV function and GBM growth and invasion. Ectopic expression of miR-1 in GBM cells blocked in vivo growth, neovascularization and invasiveness. These effects were associated with a role for miR-1 in intercellular communication in the microenvironment mediated by EVs released by cancer stem-like GBM cells. An EV-dependent phenotype defined by GBM invasion, neurosphere growth and endothelial tube formation was mitigated by loading miR-1 into GBM-derived EVs. Protein cargo in EVs was characterized to learn how miR-1 directed EV function. The mRNA encoding Annexin A2 (ANXA2), one of the most abundant proteins in GBM-derived EVs, was found to be a direct target of miR-1 control. In addition, EV-derived miR-1 along with other ANXA2 EV networking partners targeted multiple pro-oncogenic signals in cells within the GBM microenvironment. Together, our results showed how EV signalling promotes the malignant character of GBM and how ectopic expression of miR-1 can mitigate this character, with possible implications for how to develop a unique miRNA-based therapy for GBM management.Cancer Research 12/2013; · 9.28 Impact Factor