Resistin effects on pancreatic cancer progression and chemoresistance are mediated through its receptors CAP1 and TLR4

Resistin, secreted by macrophages in tumor microenvironment, has never been investigated in pancreatic cancer models, despite a vibrant tumor microenvironment around pancreatic tumors. We evaluated serum resistin levels in healthy individuals versus pancreatic cancer patients representing different tumor grades. In vitro mechanistic analysis involved MiaPaCa‐2 and SW1990 cells. Resistin signaling depends on binding of resistin to its cognitive receptors. Therefore, we silenced adenylyl cyclase‐associated protein 1 (CAP1) and toll‐like receptor 4 (TLR4), its two known receptors, individually as well as in combination, by short hairpin RNA (shRNA). Effect of resistin on cell proliferation, migration, invasion, cell cycle, and sensitivity to gemcitabine was studied without or with silencing of resistin receptors CAP1 and/or TLR4. The results were also confirmed in vivo in mice xenografted with MiaPaCa‐2 cells without or with receptor silencing. We report high resistin levels in pancreatic cancer patients which correlate positively with tumor grades. We observed a marked reduction in the resistin‐induced proliferation, migration, invasion, and cell cycle of pancreatic cancer cells MiaPaCa‐2 and SW1990 when the receptors were silenced. The results were confirmed in vivo wherein resistin effects were significantly attenuated in MiaPaCa‐2 xenografts with silenced receptors. The combined silencing of CAP1 and TLR4 was found to be most effective in vitro and in vivo. We found activation of STAT3 by resistin in vivo and in vitro which was dependent on the presence of CAP1 and TLR4. Further, resistin was found to induce resistance to gemcitabine through its receptors. Our results describe novel functional roles of resistin with implications toward a better understanding of pancreatic tumor microenvironment. Resistin is secreted by macrophages in tumor microenvironment and, since, tumor microenvironment is particularly of interest in pancreatic cancer, there is need to fully understand resistin and other factors within the tumor microenvironment. Most studies have focused on exogenously added resistin, without consideration for receptors but resistin is not produced by tumor cells and, therefore, the signaling through receptors is critical. In addition to cell line‐based in vitro data, we also present in vivo and clinical data from pancreatic cancer patients, which provides validity and significance to our results.