Paracrine SDF-1α signaling mediates the effects of PSCs on GEM chemoresistance through an IL-6 autocrine loop in pancreatic cancer cells

Pancreatic cancer exhibits the poorest prognosis among all tumors and is characterized by high resistance to the currently available chemotherapeutic agents. Our previous studies have suggested that stromal components could promote the chemoresistance of pancreatic cancer cells (PCCs). Here, we explored the roles of pancreatic stellate cells (PSCs) and the SDF-1 alpha/CXCR4 axis in pancreatic cancer chemoresitance. Our results showed that primary PSCs typically expressed SDF1a, whereas its receptor CXCR4 was highly expressed in PCCs. PSC-conditioned medium (PSC-CM) inhibited Gemcitabine (GEM)-induced cytotoxicity and apoptosis in the human PCC line Panc-1, which was antagonized by an SDF-1 alpha neutralizing Ab. Recombinant human SDF-1 alpha (rhSDF-1 alpha) increased IL-6 expression and secretion in Panc-1 cells in a time and dose-dependent manner, and this effect was suppressed by the CXCR4 antagonist AMD3100. rhSDF-1 alpha protected Panc-1 cells from GEM-induced apoptosis, and the protective effect was significantly reduced by blocking IL-6 using a neutralizing antibody. Moreover, rhSDF-1 alpha increased FAK, ERK1/2, AKT and P38 phosphorylation in Panc-1 cells, and either FAK or ERK1/2 inhibition suppressed SDF-1 alpha-upregulated IL-6 expression. SDF-1 alpha-induced AKT activation was almost completely blocked by FAK inhibition. In conclusion, we demonstrate for the first time that PSCs promote the chemoresistance of PCCs to GEM, and this effect is mediated by paracrine SDF-1 alpha/CXCR4 signaling-induced activation of the intracellular FAK-AKT and ERK1/2 signaling pathways and a subsequent IL-6 autocrine loop in PCCs. Our findings indicate that blocking the PSC-PCC interaction by inhibiting SDF-1 alpha/CXCR4 signaling may be a promising therapeutic strategy for overcoming chemoresistance in pancreatic cancer.