Hepatic Stellate Cell Coculture Enables Sorafenib Resistance in Huh7 Cells through HGFc-MetAkt and Jak2Stat3 Pathways
Joint Authors
Jiang, Chunping
Chen, Weibo
Wang, Zhongxia
Ding, Yitao
Zhang, Guang
Wu, Junhua
Shi, Hua
Cao, Yin
Source
Issue
Vol. 2014, Issue 2014 (31 Dec. 2014), pp.1-10, 10 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2014-06-25
Country of Publication
Egypt
No. of Pages
10
Main Subjects
Abstract EN
Purpose.
Tumor microenvironment confers drug resistance to kinase inhibitors by increasing RKT ligand levels that result in the activation of cell-survival signaling including PI3K and MAPK signals.
We assessed whether HSC-LX2 coculture conferred sorafenib resistance in Huh7 and revealed the mechanism underlying the drug resistance.
Experimental Design.
The effect of LX2 on sorafenib resistance was determined by coculture system with Huh7 cells.
The rescue function of LX2 supernatants was assessed by MTT assay and fluorescence microscopy.
The underlying mechanism was tested by administration of pathway inhibitors and manifested by Western blotting.
Results.
LX2 coculture significantly induced sorafenib resistance in Huh7 by activating p-Akt that led to reactivation of p-ERK.
LX2 secreted HGF into the culture medium that triggered drug resistance, and exogenous HGF could also induce sorafenib resistance.
The inhibition of p-Akt blocked sorafenib resistance caused by LX2 coculture.
Increased phosphorylation of Jak2 and Stat3 was also detected in LX2 cocultured Huh7 cells.
The Jak inhibitor tofacitinib reversed sorafenib resistance by blocking Jak2 and Stat3 activation.
The combined administration of sorafenib and p-Stat3 inhibitor S3I-201 augmented induced apoptosis even in the presence of sorafenib resistance.
Conclusions.
HSC-LX2 coculture induced sorafenib resistance in Huh7 through multiple pathways: HGF/c-Met/Akt pathway and Jak2/Stat3 pathway.
A combined administration of sorafenib and S3I-201 was able to augment sorafenib-induced apoptosis even in the presence of LX2 coculture.
American Psychological Association (APA)
Chen, Weibo& Wu, Junhua& Shi, Hua& Wang, Zhongxia& Zhang, Guang& Cao, Yin…[et al.]. 2014. Hepatic Stellate Cell Coculture Enables Sorafenib Resistance in Huh7 Cells through HGFc-MetAkt and Jak2Stat3 Pathways. BioMed Research International،Vol. 2014, no. 2014, pp.1-10.
https://search.emarefa.net/detail/BIM-497032
Modern Language Association (MLA)
Chen, Weibo…[et al.]. Hepatic Stellate Cell Coculture Enables Sorafenib Resistance in Huh7 Cells through HGFc-MetAkt and Jak2Stat3 Pathways. BioMed Research International No. 2014 (2014), pp.1-10.
https://search.emarefa.net/detail/BIM-497032
American Medical Association (AMA)
Chen, Weibo& Wu, Junhua& Shi, Hua& Wang, Zhongxia& Zhang, Guang& Cao, Yin…[et al.]. Hepatic Stellate Cell Coculture Enables Sorafenib Resistance in Huh7 Cells through HGFc-MetAkt and Jak2Stat3 Pathways. BioMed Research International. 2014. Vol. 2014, no. 2014, pp.1-10.
https://search.emarefa.net/detail/BIM-497032
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-497032