You-Fan Peng1, Hao Lin2, De-Chen Liu2, Xiang-Yun Zhu1, Nan Huang1, Ying-Xiang Wei3, Ling Li4. 1. Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Pancreatic Research Institute, Southeast University, Nanjing, China. 2. Pancreatic Research Institute, Southeast University, Nanjing, China; Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China. 3. Department of Ultrasonic Diagnosis, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China. 4. Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Pancreatic Research Institute, Southeast University, Nanjing, China. Electronic address: liling_79@sina.com.
Abstract
BACKGROUND AND AIM: Pancreatic fibrosis increases pancreatic cancer risk in chronic pancreatitis (CP). Pancreatic stellate cells (PSCs) play a critical role in pancreatic fibrosis by transforming growth factor-β (TGFβ) 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 of Hsp90 inhibitor 17AAG in vitro. RESULTS: We observed increased expression of Hsp90 in pancreatic tissues of caerulein-induced CP mice. Hsp90 inhibitor 17AAG ameliorated pancreatic inflammation and fibrosis in caerulein-induced CP mice. In vitro, Hsp90 inhibitor 17AAG inhibited TGFβ1-induced activation and extracellular matrix accumulation of PSCs by blocking TGFβR-mediated Smad2/3 and PI3K /Akt/GSK-3β signaling pathways.Hsp90 inhibitor 17AAG degraded TGFβRII by a ubiquitin-proteasome pathway, co-immunoprecipitation showed an interaction between Hsp90 and TGFβRII 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.
BACKGROUND AND AIM: Pancreatic fibrosis increases pancreatic cancer risk in chronic pancreatitis (CP). Pancreatic stellate cells (PSCs) play a critical role in pancreatic fibrosis by transforming growth factor-β (TGFβ) 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 of Hsp90 inhibitor 17AAG in vitro. RESULTS: We observed increased expression of Hsp90 in pancreatic tissues of caerulein-induced CP mice. Hsp90 inhibitor 17AAG ameliorated pancreatic inflammation and fibrosis in caerulein-induced CP mice. In vitro, Hsp90 inhibitor 17AAG inhibited TGFβ1-induced activation and extracellular matrix accumulation of PSCs by blocking TGFβR-mediated Smad2/3 and PI3K /Akt/GSK-3β signaling pathways.Hsp90 inhibitor 17AAG degraded TGFβRII by a ubiquitin-proteasome pathway, co-immunoprecipitation showed an interaction between Hsp90 and TGFβRII 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.