Protein disulfide isomerase inhibition synergistically... : Hepatology (original) (raw)

Original Articles: HEPATOBILIARY MALIGNANCIES

Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma

Won, Jae‐Kyung1,2,3,†; Yu, Su Jong4,†; Hwang, Chae Young1,†; Cho, Sung‐Hwan1; Park, Sang‐Min1; Kim, Kwangsoo5; Choi, Won‐Mook4; Cho, Hyeki4; Cho, Eun Ju4; Lee, Jeong‐Hoon4; Lee, Kyung Bun3; Kim, Yoon Jun4; Suh, Kyung‐Suk6; Jang, Ja‐June3; Kim, Chung Yong4; Yoon, Jung‐Hwan4,‡; Cho, Kwang‐Hyun*,1,2,‡

1Laboratory for Systems Biology and Bio‐inspired EngineeringDepartment of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST)DaejeonKorea

2Graduate School of Medical Science and Engineering, KAISTDaejeonKorea

3Department of PathologySeoul National University Hospital, Seoul National University College of MedicineSeoulKorea

4Department of Internal Medicine and Liver Research InstituteSeoul National University College of MedicineSeoulKorea

5Division of Clinical BioinformaticsBiomedical Research Institute, Seoul National University HospitalSeoulKorea

6Department of SurgerySeoul National University Hospital, Seoul National University College of MedicineSeoulKorea

* ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Kwang‐Hyun Cho, Ph.D.
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST)
291 Daehak‐ro, Yuseong‐gu, Daejeon 34141, Republic of Korea
E‐mail: [email protected]
Tel: +82‐42‐350‐4325

†These three authors equally contributed to this work.

‡These two authors equally contributed to this work.

Abstract

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 pathogenetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCCs. In this study, we utilized 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 list functional enrichment analysis and gene set enrichment analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum 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. Conclusion: 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. (Hepatology 2017;66:855–868).