STAT3 Mediates Regorafenib-Induced Apoptosis in Hepatocellular Carcinoma

Abstract

Purpose: Here, we aim to investigate the molecular mechanism of regorafenib and verify the potential druggable target for the treatment of hepatocellular carcinoma (HCC).Experimental Design: HCC cell lines (PLC5, HepG2, Hep3B, SK-Hep1, and HA59T) were used to investigate the in vitro effect of regorafenib. Phosphatase activity was analyzed in HCC cells and purified SHP-1 proteins. PLC5-bearing mice were used to test the therapeutic efficiency of 20 and 40 mg/kg/d treatment with regorafenib (n ! 8 mice). The clinical relevance of STAT3 signaling was investigated with 142 tumor samples from different patients with HCC. Descriptive statistical analysis was used to compare the baseline characteristics of patients and the expression of p-STAT3.Results: Regorafenib inhibited STAT3-related signaling in a dose-dependent manner and was a more potent inhibitor of STAT3 than sorafenib. Regorafenib increased SHP-1 phosphatase activity in purified SHP-1 protein directly. N-SH2 domain deletion and D61A mutants mimicking open-form SHP-1 partially abolished regorafenib-induced STAT3 inhibition and apoptosis. Importantly, a higher level of expression of STAT3 was found in patients with advanced clinical stages (P ¼ 0.009) and poorly differentiated tumors (P ¼ 0.035).Conclusions: Regorafenib induced significant tumor inhibition by relieving the autoinhibited N-SH2 domain of SHP-1 directly and inhibiting p-STAT3 signals. STAT3 may be suitable as a prognostic marker of HCC development, and may be a druggable target for HCC-targeted therapy using regorafenib. Clin Cancer Res; 20(22); 5768-76. Ó2014 AACR.

Regorafenib diminishes the expression and secretion of angiogenesis and metastasis associated proteins and inhibits cell invasion via NF-κB inactivation in SK-Hep1 cells

“…Regorafenib, a novel sorafenib derivative, has been approved by the Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer and advanced gastrointestinal stromal tumors (18). Our previous studies indicated that sorafenib, as an NF-κB signal inhibitor, inhibits the vorinostatand 12-O-tetradecanoylphorbol-13-acetate-induced expression of angiogenesis-and metastasis-associated proteins through the inhibition of NF-κB activation in HCC cells in vitro and in vivo (13,19).…”

“…Regorafenib has been approved for the treatment of metastatic colorectal cancer and advanced gastrointestinal stromal tumors. A randomized double-blinded phase III study of regorafenib in patients with HCC who have progressed after sorafenib treatment is ongoing (18). In our previous studies, sorafenib was revealed to be an inhibitor of NF-κB signaling and reduced NF-κB-modulated expression of proteins including MMP-9 and VEGF in HCC in vitro and in vivo (13,19).…”

Stat3 is a candidate epigenetic biomarker of perinatal Bisphenol A exposure associated with murine hepatic tumors with implications for human health

“…26 Further, a STAT3-dependent inflammatory feedback loop has been implicated in epigenetic control of transformation. 27 STAT3 has previously been implicated as a prognostic indicator of HCC progression in humans 28 and is currently being tested as a pharmacologic target in HCC therapy. 28,29 This transcription factor also plays a role in cellular differentiation.…”

“…27 STAT3 has previously been implicated as a prognostic indicator of HCC progression in humans 28 and is currently being tested as a pharmacologic target in HCC therapy. 28,29 This transcription factor also plays a role in cellular differentiation. Temporarily increased expression of hormone-dependent STAT3 in primed human pluripotent stem cells stimulates cells to undergo an epigenetic shift to na€ ıve-like pluripotency, which suggests a role in increasing the number of stem cell targets for mutational hits and eventual transformation.…”

Allicin Inhibits Proliferation and Invasion in Vitro and in Vivo via SHP-1-Mediated STAT3 Signaling in Cholangiocarcinoma

“…Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) belongs to a family of non-receptor PTPs and has been identified as a negative regulator of numerous cytokine signaling pathways [19]. Previous studies have shown that SHP-1 tyrosine phosphatase, which negatively targets phosphorylated (p)-STAT3 signaling in a wide variety of tumors, exhibits significant anti-tumor activity by triggering apoptosis and suppressing tumor formation [20][21][22]. Consequently, the STAT3 pathway may represent a target for therapeutic intervention in CCA.…”