Down-Regulation of TGF-β Expression Sensitizes the Resistance of Hepatocellular Carcinoma Cells to Sorafenib.

Content Provider	Europe PMC
Author	Kang, Dongxu Han, Zhezhu Oh, Geun-Hyeok Joo, Yeonsoo Choi, Hye Jin Song, Jae J.
Copyright Year	2017
Abstract	PurposeSorafenib, a multikinase inhibitor, is the standard therapy for patients with advanced-stage hepatocellular carcinoma (HCC). However, resistance develops to the treatment, therefore, we tried to unravel the underlying mechanism in the resistance of HCC cells to sorafenib via the development of more effective therapeutic strategies.Materials and MethodsVarious liver cancer cell lines were treated with either sorafenib only or with sorafenib after infection of adenovirus expressing short hairpin RNA (shRNA) against transforming growth factor-β (TGF-β) and p38 activity was examined using western blotting.Resultsp38 MAP kinase activity was inhibited by low concentrations of sorafenib, which could potentially lead to sorafenib resistance in HCC cell lines. Subsequently, we used constitutive form of MKK3/6 (MKK3/6E) to confirm that massive cell death was induced by the activation of p38, and demonstrated the ability to activate p38 without any stimulation. In addition, sorafenib resistance was reduced by the activation of p38. Subsequently, we confirmed that TGF-β shRNA effectively recovered the phosphorylation of p38 inhibited by sorafenib, and increased the sensitivity of HCC cells to sorafenib, thereby inducing cell death and overcoming the resistance of HCC cells to sorafenib.ConclusionOur study provides a new therapeutic strategy for HCC that overcomes the resistance of HCC to sorafenib by down-regulation of TGF-β.
ISSN	05135796
Volume Number	58
PubMed Central reference number	PMC5552643
Issue Number	5
PubMed reference number	28792132
Journal	Yonsei Medical Journal [Yonsei Med. J]
e-ISSN	19762437
DOI	10.3349/ymj.2017.58.5.899
Language	English
Publisher	Yonsei University College of Medicine
Publisher Date	2017-09-01
Access Restriction	Open
Rights License	This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. © Copyright: Yonsei University College of Medicine 2017
Subject Keyword	HCC sorafenib resistance TGF-β p38 adenovirus
Content Type	Text
Resource Type	Article
Subject	Medicine