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

Downregulation of Raf-1 kinase inhibitory protein as a sorafenib resistance mechanism in... Purpose 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. 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 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 resist- ance. Sequential combination treatment with sorafenib and PD98059 significantly reduced the viability and proliferation of sorafenib-resistant cells, while their increasing http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Cancer Research and Clinical Oncology Springer Journals

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

Loading next page...
 
/lp/springer_journal/downregulation-of-raf-1-kinase-inhibitory-protein-as-a-sorafenib-Tb0AtYJQ2F
Publisher
Springer Berlin Heidelberg
Copyright
Copyright © 2018 by Springer-Verlag GmbH Germany, part of Springer Nature
Subject
Medicine & Public Health; Oncology; Cancer Research; Internal Medicine; Hematology
ISSN
0171-5216
eISSN
1432-1335
D.O.I.
10.1007/s00432-018-2672-y
Publisher site
See Article on Publisher Site

Abstract

Purpose 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. 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 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 resist- ance. Sequential combination treatment with sorafenib and PD98059 significantly reduced the viability and proliferation of sorafenib-resistant cells, while their increasing

Journal

Journal of Cancer Research and Clinical OncologySpringer Journals

Published: Jun 1, 2018

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off