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
• 参考文献：1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase 11. International Agency for Research on Cancer. http://globocan.iarc.fr. Accessed on 23 May 2014
  2. European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908鈥?43
  3. Vandewynckel YP, Laukens D, Geerts A, Bogaerts E, Paridaens A, Verhelst X, et al. The paradox of the unfolded protein response in cancer. Anticancer Res 2013;33:4683鈥?694
  4. Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 2012;13:89鈥?02
  5. Han J, Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell聽death. Nat Cell Biol 2013;15:481鈥?90 2738" target="_blank" title="It opens in new window">CrossRef
  6. Bobrovnikova-Marjon E, Grigoriadou C, Pytel D, Zhang F, Ye J, Koumenis C, et al. PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage. Oncogene 2010;29:3881鈥?895 2010.153" target="_blank" title="It opens in new window">CrossRef
  7. Shoulders MD, Ryno LM, Genereux JC, Moresco JJ, Tu PG, Wu C, et al. Stress-independent activation of XBP1聽s and/or ATF6 reveals three functionally diverse ER-proteostasis environments. Cell Rep 2013;3:1279鈥?292 2013.03.024" target="_blank" title="It opens in new window">CrossRef
  8. Al-Rawashdeh FY, Scriven P, Cameron IC, Vergani PV, Wyld L. Unfolded protein response activation contributes to chemoresistance in hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2010;22:1099鈥?105 283378405" target="_blank" title="It opens in new window">CrossRef
  9. Shuda M. Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol 2003;38:605鈥?14 278(03)00029-1" target="_blank" title="It opens in new window">CrossRef
  10. Luk LM, Lam CT, Siu AF, Lam BY, Ng IO, Hu MY, et al. Proteomic profiling of hepatocellular carcinoma in Chinese cohort reveals heat-shock-proteins (Hsp27, Hsp70, GRP78) up-regulation and their associated prognostic values. Proteomics 2006;6:1049鈥?057 2/pmic.200500306" target="_blank" title="It opens in new window">CrossRef
  11. Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, et al. IRE1 signaling affects cell fate during the unfolded protein response. Science 2007;318:944鈥?49 26/science.1146361" target="_blank" title="It opens in new window">CrossRef
  12. Heindryckx F, Mertens K, Charette N, Vandeghinste B, Casteleyn C, Van Steenkiste C, et al. Kinetics of angiogenic changes in new mouse model for hepatocellular carcinoma. Mol Cancer 2010;9:219 219" target="_blank" title="It opens in new window">CrossRef
  13. Van de Veire S, Stalmans I, Heindryckx F, Oura H, Tijeras-Raballand A, Schmidt T, et al. Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell 2010;141:178鈥?90 2010.02.039" target="_blank" title="It opens in new window">CrossRef
  14. Korennykh AV, Egea PF, Korostelev AA, Finer-Moore J, Zhang C, Shokat KM, et al. The unfolded protein response signals through high-order assembly of Ire1. Nature 2009;457:687鈥?93 CrossRef
  15. Harding HP, Zyryanova AF, Ron D. Uncoupling proteostasis and development in vitro with a small molecule inhibitor of the pancreatic endoplasmic reticulum kinase, PERK. J Biol Chem 2012;287:44338鈥?4344 2.428987" target="_blank" title="It opens in new window">CrossRef
  16. Kanzler S, Galle PR. Apoptosis and the liver. Semin Cancer Biol 2000;10:173鈥?84 2000.0318" target="_blank" title="It opens in new window">CrossRef
  17. Hosokawa N, Wada I, Natsuka Y, Nagata K. EDEM accelerates ERAD by preventing aberrant dimer formation of misfolded alpha1-antitrypsin. Genes Cells 2006;11:465鈥?76 2443.2006.00957.x" target="_blank" title="It opens in new window">CrossRef
  18. Dezwaan-McCabe D, Riordan JD, Arensdorf AM, Icardi MS, Dupuy AJ, Rutkowski DT. The stress-regulated transcription factor CHOP promotes hepatic inflammatory gene expression, fibrosis, and oncogenesis. PLoS Genet 2013;9:e1003937 CrossRef
  19. Scaiewicz V, Nahmias A, Chung RT, Mueller T, Tirosh B, Shibolet O. CCAAT/enhancer-binding protein homologous (CHOP) protein promotes carcinogenesis in the DEN-induced hepatocellular carcinoma model. PLoS ONE 2013;8:e81065 CrossRef
  20. Ghosh D, Choudhury ST, Ghosh S, Mandal AK, Sarkar S, Ghosh A, et al. Nanocapsulated curcumin: oral chemopreventive formulation against diethylnitrosamine-induced hepatocellular carcinoma in rat. Chem Biol Interact 2012;195:206鈥?14 2011.12.004" target="_blank" title="It opens in new window">CrossRef
  21. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 2003;11:619鈥?33 2765(03)00105-9" target="_blank" title="It opens in new window">CrossRef
  22. Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, et al. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 2005;307:935鈥?39 26/science.1101902" target="_blank" title="It opens in new window">CrossRef
  23. Wang C, Jiang K, Gao D, Kang X, Sun C, Zhang Q, et al. Clusterin protects hepatocellular carcinoma cells from ER-stress-induced apoptosis through GRP78. PLoS ONE 2013;8:e55981 CrossRef
  24. Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 2000;5:897鈥?04 2765(00)80330-5" target="_blank" title="It opens in new window">CrossRef
  25. Zhang P, McGrath B, Li S, Frank A, Zambito F, Reinert J, et al. The PERK eukaryotic initiation factor 2伪 kinase is required for the development of the skeletal system, postnatal growth, and function and viability of the pancreas. Mol Cell Biol 2002;22:3864鈥?874 28/MCB.22.11.3864-3874.2002" target="_blank" title="It opens in new window">CrossRef
  
• 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.