Insulin-like growth factor binding protein 3 chemosensitizes pancreatic ductal adenocarcinoma through its death receptor

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. Gemcitabine and doxorubicin are commonly used as the chemotherapy agents, but most of PDAC tumors eventually acquired resistance to chemotherapy. Accumulating evidence indicates that Insulin-like growth factor binding protein 3 (IGFBP-3) plays a key role against tumor growth but its expression has commonly suppressed. The present study was designed to evaluate IGFBP-3 effects in chemotherapy sensitization of PDAC cells. Here, we report that the re-sensitization of chemoresistant PDAC cells was occurred by IGFBP-3 through recruitment of its death receptor (IGFBP-3R). Using gemcitabine, doxorubicin-resistant PDAC cell lines, we found that IGFBP-3 sensitized chemoresistant cells by activating apoptosis (as evaluated by Bax up-regulation, Bcl-2 down-regulation as well as Caspase-3 and Caspase 8 activation). IGFBP-3R was also found to have higher expression level in resistant AsPc-1 and MIA PaCa-2 cells in comparison to parental cells. IGFBP-3R was also highly expressed in PDAC tumor which exposed to chemotherapy in comparison to un-treated PDAC tumors. In addition, we confirmed our finding by using specific siRNA to knocking down of IGFBP-3R which prevents IGFBP-3 Chemosensitization. Taken together, the present study for the first time indicates the clinical relevance for combining IGFBP-3 with chemotherapy to reduce chemoresistance in PDAC