Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress: a PERK for hepatocellular carcinoma therapy

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• 作者：Yves-Paul Vandewynckel (1)
  Debby Laukens (1)
  Eliene Bogaerts (1)
  Annelies Paridaens (1)
  Anja Van den Bussche (1)
  Xavier Verhelst (1)
  Christophe Van Steenkiste (1)
  Benedicte Descamps (2)
  Chris Vanhove (2) (3)
  Louis Libbrecht (4)
  Riet De Rycke (3) (5)
  Bart N. Lambrecht (3) (5) (6)
  Anja Geerts (1)
  Sophie Janssens (3) (5) (6)
  Hans Van Vlierberghe (1)
  
  1. Department of Hepatology and Gastroenterology ; Ghent University ; De Pintelaan 185 ; 1K12聽IE ; 9000 ; Ghent ; Belgium
  2. Infinity Imaging Lab ; Ghent University ; De Pintelaan 185 ; 9000 ; Ghent ; Belgium
  3. GROUP-ID Consortium ; Ghent University Hospital ; Ghent University ; De Pintelaan 185 ; 9000 ; Ghent ; Belgium
  4. Department of Pathology ; Ghent University ; De Pintelaan 185 ; 9000 ; Ghent ; Belgium
  5. Unit Immunoregulation and Mucosal Immunology ; VIB Inflammation Research Center ; Technologiepark 927 ; 9052 ; Ghent ; Belgium
  6. Department of Respiratory Medicine ; Ghent University Hospital ; Ghent University ; De Pintelaan 185 ; 9000 ; Ghent ; Belgium
  
• 关键词：Liver neoplasm ; Endoplasmic reticulum ; Stress ; HepG2 cells ; PERK kinase ; Inositol ; requiring enzyme ; 1
• 刊名：Hepatology International
• 出版年：2015
• 出版时间：January 2015
• 年：2015
• 卷：9
• 期：1
• 页码：93-104
• 全文大小：3,226 KB
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• 刊物主题：Hepatology; Colorectal Surgery; Surgery;
• 出版者：Springer India
• ISSN：1936-0541

文摘

Background Functional disturbances of the endoplasmic reticulum (ER) lead to activation of the unfolded protein response (UPR), which is involved in the consecutive steps of carcinogenesis. In human hepatocellular carcinoma (HCC), the UPR is shown to be activated; however, little is known about the UPR kinetics and effects of UPR modulation in HCC. Methods We sequentially monitored the UPR over time in an orthotopic mouse model for HCC and explored the effects of UPR modulation on cell viability and proliferation in vitro and in the mouse model. Results The expression of ER-resident chaperones peaked during tumor initiation and increased further during tumor progression, predominantly within the nodules. A peak in Ire1 signaling was observed during tumor initiation. The Perk pathway was activated during tumor progression, and the proapoptotic target Chop was upregulated from week 5 and continued to rise, especially in the tumors. The Atf6 pathway was modestly activated only after tumor initiation. Consistent with the UPR activation, electron microscopy demonstrated ER expansion and reorganization in HCC cells in vivo. Strikingly, under ER stress or hypoxia, the Perk inhibitor and not the Ire1 inhibitor reduced cell viability and proliferation via escalating proteotoxic stress in vitro. Notably, the Perk inhibitor significantly decreased tumor burden in the mouse model. Conclusion We provide the first evaluation of the UPR dynamics in a long-term cancer model and identified a small molecule inhibitor of Perk as a promising strategy for HCC therapy.