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World J Gastroenterol. Nov 7, 2014; 20(41): 15269-15274
Published online Nov 7, 2014. doi: 10.3748/wjg.v20.i41.15269
Downregulation of signal transducer and activator of transcription 3 by sorafenib: A novel mechanism for hepatocellular carcinoma therapy
Man-Hsin Hung, Wei-Tien Tai, Chung-Wai Shiau, Kuen-Feng Chen
Man-Hsin Hung, Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan
Man-Hsin Hung, Program in Molecular Medicine, School of Life Sciences, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan
Wei-Tien Tai, Kuen-Feng Chen, Department of Medical Research, National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei 100, Taiwan
Chung-Wai Shiau, Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan
Author contributions: Hung MH wrote the manuscript and generated the figures; Tai WT and Shiau CW contributed to the writing and editing of the manuscript; Chen KF generated the idea and designed the aims of this review and wrote the manuscript.
Correspondence to: Kuen-Feng Chen, MD, PhD, Department of Medical Research, National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan. kfchen1970@ntu.edu.tw
Telephone: +886-2-23123456 Fax: +886-2-23225329
Received: March 19, 2014
Revised: May 7, 2014
Accepted: June 12, 2014
Published online: November 7, 2014
Processing time: 236 Days and 18.9 Hours
Abstract

Hepatocellular carcinoma is one of the most common cancers worldwide, and a leading cause of cancer-related death. Owing to unsatisfactory clinical outcomes under the current standard of care, there is a need to search for and identify novel and potent therapeutic targets to improve patient outcomes. Sorafenib is the first and only approved targeted therapy for the treatment of hepatocellular carcinoma. Besides functioning as a multiple tyrosine kinase, sorafenib also acts via a kinase-independent mechanism to target signal transducer and activator of transcription 3 (STAT3) signaling in hepatocellular carcinoma cells. STAT3 is a key regulator of inflammation, cell survival, and tumorigenesis of liver cells, and the high percentage of hepatocellular carcinoma cells with constitutively active STAT3 justifies targeting it for the development of novel therapeutics. Sorafenib inactivates STAT3 and STAT3-related signaling by inducing a conformational change in and releasing the autoinhibition of Src homology region 2 domain-containing phosphatase-1. This phosphatase negatively regulates STAT3 activity, which leads to the subsequent apoptosis of cancer cells. The novel anti-cancer property of sorafenib will be discussed in this review, not only adding information regarding its mechanism of action but also providing an innovative approach for the development of cancer therapeutics in the future.

Keywords: Hepatocellular carcinoma; Sorafenib; Signal transducer and activator of transcription 3; Target therapy; Kinase-independent

Core tip: Hepatocellular carcinoma (HCC) is one of the major cancers worldwide, for which the only approved target therapy is sorafenib. In addition to its previously characterized kinase inhibition, sorafenib also acts via a kinase-independent mechanism to target signal transducer and activator of transcription 3 (STAT3) signaling in HCC cells. This review discusses these findings, adding to the knowledge concerning the mechanisms of action of sorafenib as well as exploring the potential use of STAT3 as a therapeutic target in future cancer drug development.