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

 Dongxu Kang  ;  Zhezhu Han  ;  Geun-Hyeok Oh  ;  Yeonsoo Joo  ;  Hye Jin Choi  ;  Jae J. Song 
 YONSEI MEDICAL JOURNAL, Vol.58(5) : 899-909, 2017 
Journal Title
Issue Date
Adenoviridae/metabolism ; Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Carcinoma, Hepatocellular/metabolism* ; Carcinoma, Hepatocellular/pathology* ; Cell Death/drug effects ; Cell Line, Tumor ; Down-Regulation/drug effects* ; Drug Resistance, Neoplasm/drug effects* ; Humans ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology* ; Mice, Inbred BALB C ; Mice, Nude ; Niacinamide/analogs & derivatives* ; Niacinamide/pharmacology ; Niacinamide/therapeutic use ; Phenylurea Compounds/pharmacology* ; Phenylurea Compounds/therapeutic use ; Phosphorylation/drug effects ; RNA, Small Interfering/metabolism ; Signal Transduction/drug effects ; Transforming Growth Factor beta/metabolism* ; Xenograft Model Antitumor Assays ; p38 Mitogen-Activated Protein Kinases/metabolism
HCC ; TGF-β ; adenovirus ; p38 ; resistance ; sorafenib
PURPOSE: Sorafenib, 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 METHODS: Various 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. RESULTS: p38 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. CONCLUSION: Our study provides a new therapeutic strategy for HCC that overcomes the resistance of HCC to sorafenib by down-regulation of TGF-β.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Song, Jae Jin(송재진) ORCID logo https://orcid.org/0000-0001-8183-9550
Choi, Hye Jin(최혜진) ORCID logo https://orcid.org/0000-0001-5917-1400
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