Downregulation of signal transducer and activator of transcription 3 by sorafenib: a novel mechanism for hepatocellular carcinoma therapy

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; Kinase-independent; Signal transducer and activator of transcription 3; Sorafenib; Target therapy.

Figure 1

Downregulation of signal transducer and activator 3 by reactivating Src homology region 2 domain-containing phosphatase 1 is an important anti-tumor property of sorafenib. Signal transducer and activator 3 (STAT3) is a key regulator that connects extrinsic carcinogenic stimulations and oncogenic signaling pathways (A). Sorafenib and its derivatives can inhibit STAT3 and STAT3-associated signaling pathways by reactivating SHP-1, a negative regulator of STAT3, in hepatocellular carcinoma cells (B).