Peng You-Fan, Lin Hao, Liu De-Chen, Zhu Xiang-Yun, Huang Nan, Wei Ying-Xiang, Li Ling
Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Pancreatic Research Institute, Southeast University, Nanjing, China.
Pancreatic Research Institute, Southeast University, Nanjing, China; Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
Cell Signal. 2021 Aug;84:110001. doi: 10.1016/j.cellsig.2021.110001. Epub 2021 Apr 1.
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.
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.
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.
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.
胰腺纤维化会增加慢性胰腺炎（CP）患者患胰腺癌的风险。胰腺星状细胞（PSC）在胰腺纤维化过程中起关键作用，转化生长因子-β（TGFβ）已被证明可抑制转化生长因子-β受体（TGFβR）介导的Smad和非Smad信号通路。因此，本研究在CP小鼠中评估了热休克蛋白90（Hsp90）抑制剂对胰腺纤维化的影响，并在体外进一步研究了Hsp90与PSC生物学功能之间的关联。
在雨蛙素诱导的CP小鼠中评估Hsp90抑制剂17AAG对胰腺纤维化的影响，并使用原代PSC在体外确定Hsp90抑制剂17AAG的作用。
我们观察到雨蛙素诱导的CP小鼠胰腺组织中Hsp90表达增加。Hsp90抑制剂17AAG改善了雨蛙素诱导的CP小鼠的胰腺炎症和纤维化。在体外，Hsp90抑制剂17AAG通过阻断TGFβR介导的Smad2/3和PI3K/Akt/GSK-3β信号通路，抑制TGFβ1诱导的PSC活化和细胞外基质积累。Hsp90抑制剂17AAG通过泛素-蛋白酶体途径降解TGFβRII，免疫共沉淀显示Hsp90与PSC中的TGFβRII存在相互作用。
该研究表明，Hsp90抑制剂17AAG可显著预防雨蛙素诱导的CP小鼠胰腺纤维化的发展，并在体外抑制PSC的活化和细胞外基质积累。目前的结果为基于抑制Hsp90治疗CP胰腺纤维化提供了一种潜在的治疗策略。
