Blocking gp130-mediated IL-6 and Oncostatin M signaling inhibits pancreatic tumor growth in vivo

Einleitung Glycoprotein 130 (gp130) is a compound of the Interleukin-6 (IL-6) and Oncostatin M (OSM) receptor complex. IL-6 or OSM signaling via the major downstream effector STAT3 is protumorigenic in pancreatic ductal adenocarcinoma (PDAC). Previous studies indicate raloxifene as potential inhibitor of IL-6/gp130 interaction. The novel small molecule gp130 inhibitor (SC144) was discovered recently with a broad-spectrum anticancer activity.

Ziele We examine the effects of raloxifene and SC144 on PDAC growth and the role in IL-6 and OSM induced STAT3 phosphorylation.

Methodik Inhibition of IL-6 or OSM induced STAT3 phosphorylation by raloxifene or SC144 was assessed in the L3.6pl human pancreatic cancer cell line by Western blotting. Drug affinity responsive target stability (DARTS) assay was performed to identify protein-ligand interaction between gp130 and raloxifene or SC144. In a human PDAC BALB/c nu/nu xenograft model, raloxifene or SC144 were administered intraperitoneally and orthotopic and metastatic tumor growth was monitored.

Ergebnis Treatment with raloxifene or SC144 inhibited both IL-6 and OSM induced STAT3 phosphorylation in L3.6pl cells in a dose- and time-dependent manner. Raloxifene and SC144 were shown to be bound to gp130, reducing the protease susceptibility of gp130. In a PDAC tumor xenograft model, administration of raloxifene or SC144 significantly suppressed orthotopic and metastatic tumor growth.

Schlussfolgerung Raloxifene and SC144 interact and suppress both IL-6 and OSM/gp130/STAT3 signaling pathway in a PDAC cell line and inhibit tumor growth in vivo. These results suggest gp130 as a promising drug target for pancreatic cancer therapy. Taken together, our results suggest that targeting gp130/STAT3 signaling with raloxifene or SC144 may be an effective treatment strategy for the treatment of PDAC patients.

Publication History

Article published online:
07 September 2021