KLI

간암 환자의 sorafenib 내성 메커니즘에서 Raf-1 Kinase억제 단백의 downregulation

Metadata Downloads
Abstract
Introduction: 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.
Materials and methods: 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.
Results: 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 (Raf kinase inhibitory protein) 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.
Conclusions: Our findings suggested that 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.
Author(s)
최광현
Issued Date
2017
Awarded Date
2018-02
Type
Dissertation
URI
https://oak.ulsan.ac.kr/handle/2021.oak/6441
http://ulsan.dcollection.net/common/orgView/200000009706
Affiliation
울산대학교
Department
일반대학원 의학과
Advisor
이한주
Degree
Doctor
Publisher
울산대학교 일반대학원 의학과
Language
eng
Rights
울산대학교 논문은 저작권에 의해 보호받습니다.
Appears in Collections:
Medicine > 2. Theses (Ph.D)
Authorize & License
  • Authorize공개
Files in This Item:

Items in Repository are protected by copyright, with all rights reserved, unless otherwise indicated.