LAUSR

BACKGROUND AND AIM Pancreatic fibrosis increases pancreatic cancer risk in chronic pancreatitis (CP). Pancreatic stellate cells (PSCs) play a critical role in the pathological processes of pancreatic fibrosis by transforming growth factor β (TGFβ) signal pathway in CP. Heat-shock protein 90 (Hsp90) inhibitor has been shown to inhibit transforming growth factor β receptor (TGFβR)-mediated Smad and no-Smad signaling pathways. Thus, the effects of Hsp90 inhibitor on pancreatic fibrosis are evaluated in CP mice, and the association between Hsp90 and biological functions of PSCs is further investigated in vitro. METHODS The effects of Hsp90 inhibitor 17AAG on pancreatic fibrosis were assessed in caerulein-induced CP mice, and primary PSCs were used to determine the role Hsp90 inhibitor 17AAG. RESULTS We observed increased expression of Hsp90 in pancreatic tissue of caerulein-induced CP mice. Hsp90 inhibitor 17AAG ameliorated inflammation and pancreatic fibrosis in caerulein-induced CP mice. In vitro, Hsp90 inhibitor 17AAG inhibited TGF-β1-induced activation and extracellular matrix accumulation of PSCs by blocking TGFβR-mediated Smad2/3 and PI3K /Akt/GSK-3β signaling pathways. Hsp90 inhibitor 17AAG disrupted the interaction between Hsp90 and TGFβRII, and degraded TGFβRII by a ubiquitin proteasome pathway in PSCs. CONCLUSIONS The study suggests that an Hsp90 inhibitor 17AAG remarkable prevents the development of pancreatic fibrosis in caerulein-induced CP mice, and suppresses activation and extracellular matrix accumulation of PSCs in vitro. The current results provide a potential treatment strategy based on Hsp90 inhibition for pancreatic fibrosis in CP.