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| Status |
Public on Mar 19, 2017 |
| Title |
Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma [SNU761] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients’ survival gain is limited and varies over a wide range depending on patho-genetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucuial to achieve efficient control of HCCs. In this study, we employed a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene ontology and gene set analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum (ER) stress network model combined with in vitro experiments showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low PDI expression group. These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness.
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| Overall design |
Total RNA was extracted from cultured cells and subjected to RT-PCR analysis. HCC cell lines (SNU761, Huh7, Hep3B and HepG2) were treated with sorafenib 3 mM for 24 hours, while the control group was treated with only DMSO.
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| Contributor(s) |
Won J, Yu SJ, Hwang CY, Yoon J, Cho K |
| Citation(s) |
28439950 |
| |
| Submission date |
Mar 18, 2017 |
| Last update date |
Jun 18, 2017 |
| Contact name |
Jae-Kyung Won |
| E-mail(s) |
jkwon@snuh.org
|
| Organization name |
Seoul National University Hospital
|
| Street address |
101 Daehak-ro
|
| City |
Seoul |
| ZIP/Postal code |
110-744 |
| Country |
South Korea |
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| Platforms (1) |
| GPL10904 |
Illumina HumanHT-12 V4.0 expression beadchip (gene symbol) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE96796 |
Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma |
|
| Relations |
| BioProject |
PRJNA379716 |
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