IL-6 is associated to IGF-1Ec upregulation and Ec peptide secretion, from prostate tumors.

BACKGROUND: Ec peptide (PEc), resulting from the proteolytic cleavage of the IGF-1Ec isoform, is involved in prostate cancer progression and metastasis, whereas in muscle tissue, it is associated with the mobilization of satellite cells prior to repair. Our aim is to determine the physiological conditions associated to the IGF-1Ec upregulation and PEc secretion in prostate tumors, as well as, the effect of tumor PEc on tumor repair. METHODS: IGF-1 (mature and isoforms) expression was examined by qRT-PCR, both in prostate cancer cells co-incubated with cells of the immune response (IR) and in tumors. PEc secretion was determined by Multiple Reaction Monitoring. The effect of PEc, on mesenchymal stem cell (MSC) mobilization and repair, was examined using migration and invasion assays, FISH and immunohistochemistry (IHC). The JAK/STAT signaling pathway leading to the IGF1-Ec expression was examined by western blot analysis. Determination of the expression and localization of IL-6 and IGF-1Ec in prostate tumors was examined by qRT-PCR and by IHC. RESULTS: We documented that IL-6 secreted by IR cells activates the JAK2 and STAT3 pathway through IL-6 receptor in cancer cells, leading to the IGF-1Ec upregulation and PEc secretion, as well as to the IL-6 expression and secretion. The resulting PEc, apart from its oncogenic role, also mobilizes MSCs towards the tumor, thus promoting tumor repair. CONCLUSIONS: IL-6 leads to the PEc secretion from prostate cancer cells. Apart from its oncogenic role, PEc is also involved in the mobilization of MSCs resulting in tumor repair.

Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway.

Interactions between Eph receptor tyrosine kinases (RTKs) and membrane-anchored ephrin ligands critically regulate axon pathfinding and development of the cardiovascular system, as well as migration of neural cells. Similar to other RTKs, ligand-activated Eph kinases recruit multiple signalling and adaptor proteins, several of which are involved in growth regulation. However, in contrast to other RTKs, activation of Eph receptors fails to promote cell proliferation or to transform rodent fibroblasts, indicating that Eph kinases may initiate signalling pathways that are distinct from those transmitted by other RTKs. Here we show that stimulation of endogenous EphA kinases with ephrin-A1 potently inhibits the Ras/MAPK cascade in a range of cell types, and attenuates activation of mitogen-activated protein kinase (MAPK) by receptors for platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF). In prostatic epithelial cells and endothelial cells, but not fibroblasts, treatment with ephrin-A1 inhibits cell proliferation. Our results identify EphA kinases as negative regulators of the Ras/MAPK pathway that exert anti-mitogenic functions in a cell-type-specific manner.