Journal of Cancer Research and Clinical Oncology

, Volume 144, Issue 8, pp 1487–1501 | Cite as

Downregulation of Raf-1 kinase inhibitory protein as a sorafenib resistance mechanism in hepatocellular carcinoma cell lines

  • Jin Sun Kim
  • Gwang Hyeon Choi
  • Yusun Jung
  • Kang Mo KimEmail author
  • Se-Jin Jang
  • Eun Sil Yu
  • Han Chu Lee
Original Article – Cancer Research



Although sorafenib enhances overall survival, sorafenib resistance has been reported to be a significant limiting factor for improved prognosis in patients with hepatocellular carcinoma (HCC). Therefore, it is important to identify the mechanism of sorafenib resistance. This study aimed to identify the causative factor of sorafenib resistance and suggest methods for overcoming it.


The sensitivity to sorafenib was compared in human HCC cell lines and patient-derived HCC primary cells. Based on its cytotoxicity, signaling pathways altered by sorafenib and the causative factors were examined through assays. The mechanism by which sorafenib modified the sorafenib-resistance inducer through gene or protein expression or stability was also investigated. We also designed a treatment option to overcome sorafenib resistance.


Sorafenib activated the Raf/MEK/ERK pathway and caused sorafenib resistance in HCC cell lines and patient-derived HCC primary cells. Sorafenib reactivated the MAPK pathway by down-regulating RKIP at the post-translational level. Knockdown of RKIP increased phosphorylated ERK and thus suppressed sorafenib-mediated cell death. We also found that sorafenib-reactivated ERK maybe an attractive target for second-line therapy for patients with sorafenib resistance. Sequential combination treatment with sorafenib and PD98059 significantly reduced the viability and proliferation of sorafenib-resistant cells, while their increasing apoptosis efficacy.


Reactivation of the Raf/MEK/ERK pathway through aberrant expression of RKIP is one of the mechanisms behind sorafenib resistance in HCC. Sequential combination treatment with sorafenib and PD98059 could provide a new strategy to overcome sorafenib resistance in future clinical studies.


Hepatocellular carcinoma Sorafenib Resistance Raf-1 kinase inhibitory protein Sequential treatment 



The authors were supported by research funding from the Asan Institute for Life Sciences (2014-399 to KM Kim).

Author contributions

JSK, GHC and KMK performed the majority of experimental and analyzed the data; JSK, GHC and YJ performed the investigations; JSK, GHC, S-JJ, ESY and KMK designed and coordinated the research; JSK, GHC and KMK wrote the paper.


This study funded by the Asan Institute for Life Sciences (2014-399 to KM Kim).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants of animals performed by any of the authors.

Supplementary material

432_2018_2672_MOESM1_ESM.docx (98 kb)
Supplementary material 1 (DOCX 98 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Gastroenterology, Asan Liver Center, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulSouth Korea
  2. 2.Department of Pathology, Asan Liver Center, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulSouth Korea

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