RN1, a novel galectin-3 inhibitor, inhibits pancreatic cancer cell growth in vitro and in vivo via blocking galectin-3 associated signaling pathways
【摘要】：Galectin-3(Gal-3) has been implicated in pancreatic ductal adenocarcinoma(PDAC), and its candidacy as a therapeutic target has been evaluated. Gal-3 is widely up-regulated in tumors,and its expression is associated with the development and malignancy of PDAC. In the present study, we demonstrate that a polysaccharide, RN1, purified from the flower of Panax notoginseng binds to Gal-3 and suppresses its expression. In addition, RN1 markedly inhibits PDAC cells growth in vitro, in vivo and in patient-derived xenografts(PDXs). Mechanistically, RN1 binds to epidermal growth factor receptor(EGFR) and Gal-3, thereby disrupting the interaction between Gal-3 and EGFR and down-regulating ERK phosphorylation and the transcription factor of Gal-3,Runx1 expression. Inhibiting the expression of Runx1 by RN1, suppresses Gal-3 expression and inactivates Gal-3-associated signaling pathways, including the EGFR/ERK/Runx1,BMP/smad/Id-3 and integrin/FAK/JNK signaling pathways. In addition, RN1 can also bind to bone morphogenetic protein receptors(BMPR1A and BMPR2) and block the interaction between Gal-3 and the BMPRs. Thus, our results suggest that a novel Gal-3 inhibitor RN1 may be a potential candidate for human PDAC treatment via multiple targets and multiple signaling pathways.
【作者单位】：Glycochemistry & Glycobiology Lab, Shanghai Institute of Materia Medica, Chinese Academy of Sciences State Key Laboratory of Natural Medicines, China Pharmaceutical University Department of General Surgery, Changzheng Hospital, Second Military Medical University