Abstract
Inflammation is a major driver of tumor progression and metastasis, although the mechanisms by which proinflammatory cytokines drive metastatic invasion are unknown. Interleukin-6 (IL-6) is a potent proinflammatory cytokine that is elevated in individuals with pancreatic cancer (PDAC), is required for PDAC progression in mice, and increases tumor cell invasion in vitro Here, we provide insights into the mechanisms by which IL-6 activates tumor cell invasion. We found that IL-6 stimulation rapidly and robustly activates the small GTPase cell division cycle 42 (CDC42) in human PDAC cells and promotes the formation of premigratory filopodia. The CDC42 activation was required for IL-6-induced invasion as blocking CDC42 activity rendered the cells insensitive to IL-6's proinvasive effects. Loss of Janus kinase 2 (JAK2) or signal transducer and activator of transcription 3 (STAT3) prevented IL-6-mediated CDC42 activation, indicating that IL-6 activates CDC42 through both JAK2 and STAT3. However, the rapid activation of CDC42 suggested that this activation may be distinct from canonical STAT3-mediated transcriptional activation. Importantly, we observed an interaction between STAT3 and IQ motif-containing GTPase-activating protein 1 (IQGAP1), a scaffolding platform that binds CDC42. STAT3 colocalized with CDC42 and IQGAP1 at the plasma membrane, suggesting cross-talk between IL-6-mediated STAT3 signaling and CDC42 activation. These results suggest that IL-6 promotes metastatic invasion, at least partially, through CDC42 and that, along with its pleiotropic effects on tumor growth and progression, IL-6 signaling also activates proinvasive GTPase signaling, priming tumor cells for metastatic invasion.
Highlights
Inflammation is a major driver of tumor progression and metastasis, the mechanisms by which proinflammatory cytokines drive metastatic invasion are unknown
To investigate the effects of IL-6 on tumor cell invasion, pancreatic cancer cells were treated with IL-6, and their invasive properties were quantified in cell culture
The data presented here define a novel mechanism by which the inflammatory cytokine IL-6 can act directly on tumor cells to up-regulate the migratory machinery via activation of cell division cycle 42 (CDC42)
Summary
Inflammation is a major driver of tumor progression and metastasis, the mechanisms by which proinflammatory cytokines drive metastatic invasion are unknown. IL-6 can act on endothelial cells to increase angiogenesis and vascular permeability and can modtransducer and activator of transcription; IQGAP1, IQ motif– containing GTPase-activating protein 1; PanIN, pancreatic intraepithelial neoplasia; EMT, epithelial-to-mesenchymal transition; PDGF, platelet-derived growth factor; PBD, p21-binding domain; GEF, guanine nucleotide exchange factor; ERK, extracellular signal-regulated kinase; DMEM, Dulbecco’s modified Eagle’s medium; EGF, epidermal growth factor; GST, glutathione S-transferase; RBD, RhoA-binding domain. RAC1 and CDC42 regulate actin polymerization and branching that drive the formation of lamellipodia and filopodia, respectively, which are actin-based structures that are mechanical drivers of cell protrusion and migration These GTPases act at the plasma membrane and cycle between an active, GTP-bound state and an inactive, GDP-bound state. We propose a novel role for the canonical IL-6 signaling pathway in supporting metastatic dissemination in pancreatic cancer cells
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