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

Yves-Paul Vandewynckel, Debby Laukens UGent, Eliene Bogaerts, Annelies Paridaens, Anja Van den Bussche, Xavier Verhelst UGent, Christophe Van Steenkiste UGent, Benedicte Descamps UGent, Christian Vanhove UGent, Louis Libbrecht, et al. (2015) HEPATOLOGY INTERNATIONAL. 9(1). p.93-104
abstract
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. 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. 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. 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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
PROTEOSTASIS, INHIBITOR, KINASE, GROWTH, ACTIVATION, CANCER, ER-STRESS, HepG2 cells, PERK kinase, Inositol-requiring enzyme-1, Liver neoplasm, Endoplasmic reticulum, Stress, ATF6, IRE1, FATE
journal title
HEPATOLOGY INTERNATIONAL
Hepatol. Int.
volume
9
issue
1
pages
93 - 104
Web of Science type
Article
Web of Science id
000348223800014
JCR category
GASTROENTEROLOGY & HEPATOLOGY
JCR impact factor
1.125 (2015)
JCR rank
70/78 (2015)
JCR quartile
4 (2015)
ISSN
1936-0533
DOI
10.1007/s12072-014-9582-0
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
5744995
handle
http://hdl.handle.net/1854/LU-5744995
date created
2014-10-30 14:03:45
date last changed
2016-12-19 15:39:51
@article{5744995,
  abstract     = {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. 
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. 
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. 
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.},
  author       = {Vandewynckel, Yves-Paul and Laukens, Debby and Bogaerts, Eliene and Paridaens, Annelies and Van den Bussche, Anja and Verhelst, Xavier and Van Steenkiste, Christophe and Descamps, Benedicte and Vanhove, Christian and Libbrecht, Louis and De Rycke, Riet and Lambrecht, Bart and Geerts, Anja and Janssens, Sophie and Van Vlierberghe, Hans},
  issn         = {1936-0533},
  journal      = {HEPATOLOGY INTERNATIONAL},
  keyword      = {PROTEOSTASIS,INHIBITOR,KINASE,GROWTH,ACTIVATION,CANCER,ER-STRESS,HepG2 cells,PERK kinase,Inositol-requiring enzyme-1,Liver neoplasm,Endoplasmic reticulum,Stress,ATF6,IRE1,FATE},
  language     = {eng},
  number       = {1},
  pages        = {93--104},
  title        = {Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress: a PERK for hepatocellular carcinoma therapy},
  url          = {http://dx.doi.org/10.1007/s12072-014-9582-0},
  volume       = {9},
  year         = {2015},
}

Chicago
Vandewynckel, Yves-Paul, Debby Laukens, Eliene Bogaerts, Annelies Paridaens, Anja Van den Bussche, Xavier Verhelst, Christophe Van Steenkiste, et al. 2015. “Modulation of the Unfolded Protein Response Impedes Tumor Cell Adaptation to Proteotoxic Stress: a PERK for Hepatocellular Carcinoma Therapy.” Hepatology International 9 (1): 93–104.
APA
Vandewynckel, Y.-P., Laukens, D., Bogaerts, E., Paridaens, A., Van den Bussche, A., Verhelst, X., Van Steenkiste, C., et al. (2015). Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress: a PERK for hepatocellular carcinoma therapy. HEPATOLOGY INTERNATIONAL, 9(1), 93–104.
Vancouver
1.
Vandewynckel Y-P, Laukens D, Bogaerts E, Paridaens A, Van den Bussche A, Verhelst X, et al. Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress: a PERK for hepatocellular carcinoma therapy. HEPATOLOGY INTERNATIONAL. 2015;9(1):93–104.
MLA
Vandewynckel, Yves-Paul, Debby Laukens, Eliene Bogaerts, et al. “Modulation of the Unfolded Protein Response Impedes Tumor Cell Adaptation to Proteotoxic Stress: a PERK for Hepatocellular Carcinoma Therapy.” HEPATOLOGY INTERNATIONAL 9.1 (2015): 93–104. Print.