IL-24 Inhibits lung cancer cell migration and invasion by disrupting the SDF-1/CXCR4 signaling axis

© 2015 Panneerselvam et al. Background The stromal cell derived factor (SDF)-1/chemokine receptor (CXCR)-4 signaling pathway plays a key role in lung cancer metastasis and is molecular target for therapy. In the present study we investigated whether interleukin (IL)-24 can inhibit the SDF-1/CXCR4 axis and suppress lung cancer cell migration and invasion in vitro. Further, the efficacy of IL-24 in combination with CXCR4 antagonists was investigated. Methods Human H1299, A549, H460 and HCC827 lung cancer cell lines were used in the present study. The H1299 lung cancer cell line was stably transfected with doxycycline-inducible plasmid expression vector carrying the human IL-24 cDNA and used in the present study to determine the inhibitory effects of IL-24 on SDF-1/CXCR4 axis. H1299 and A549 cell lines w ere used in transient transfection studies. The inhibitory effects of IL-24 on SDF1/CXCR4 and its downstream targets were analyzed by quantitative RT-PCR, western blot, luciferase reporter assay, flow cytometry and immunocytochemistry. Functional studies included cell migration and invasion assays. Principal Findings Endogenous CXCR4 protein expression levels varied among the four human lung cancer cell lines. Doxycycline-induced IL-24 expression in the H1299-IL24 cell line resulted in reduced CXCR4 mRNA and protein expression. IL-24 post-transcriptionally regulated CXCR4 mRNA expression by decreasing the half-life of CXCR4 mRNA ( > 40%). Functional studies showed IL-24 inhibited tumor cell migration and invasion concomitant with reduction in CXCR4 and its downstream targets (pAKTS 473 , pmTORS 2448 , pPRAS40 T246 and HIF-1α). Additionally, IL-24 inhibited tumor cell migration both in the presence and absence of the CXCR4 agonist, SDF-1. Finally, IL-24 when combined with CXCR4 inhibitors (AMD3100, SJA5) or with CXCR4 siRNA demonstrated enhanced inhibitory activity on tumor cell migration. Conclusions IL-24 disrupts the SDF-1/CXCR4 signaling pathway and inhibits lung tumor cell migration and invasion. Additionally, IL-24, when combined with CXCR4 inhibitors exhibited enhanced anti-metastatic activity and is an attractive therapeutic strategy for lung metastasi

Dynamic Coupling of Near-Field and Far-Field Models

Deepwater spills pose a unique challenge for reliable predictions of oil transport and fate, since live oil spewing under very high hydrostatic pressure has characteristics remarkably distinct from oil spilling in shallow water. It is thus important to describe in detail the complex thermodynamic processes occurring in the near-field, meters above the wellhead, and the hydrodynamic processes in the far-field, up to kilometers away. However, these processes are typically modeled separately since they occur at different scales. Here we directly couple two oil prediction applications developed during the Deepwater Horizon blowout operating at different scales: the near-field Texas A&M Oilspill Calculator (TAMOC) and the far-field oil application of the Connectivity Modeling System (oil-CMS). To achieve this coupling, new oil-CMS modules were developed to read TAMOC output, which consists of the description of distinct oil droplet “types,” each of specific size and pseudo-component mixture that enters at a given mass flow rate, time, and position into the far field. These variables are transformed for use in the individual-based framework of CMS, where each droplet type fits into a droplet size distribution (DSD). Here we used 19 pseudo-components representing a large range of hydrocarbon compounds and their respective thermodynamic properties. Simulation results show that the dispersion pathway of the different droplet types varies significantly. Indeed, some droplet types remain suspended in the subsea over months, while others accumulate in the surface layers. In addition, the decay rate of oil pseudo-components significantly alters the dispersion, denoting the importance of more biodegradation and dissolution studies of chemically and naturally dispersed live oil at high pressure. This new modeling tool shows the potential for improved accuracy in predictions of oil partition in the water column and of advancing impact assessment and response during a deepwater spill

Electroweak parameters of the z0 resonance and the standard model

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