Abstract
Hepatocellular cancer (HCC) is a lethal malignancy with poor prognosis and easy recurrence. There are few agents with minor toxic side effects that can be used for treatment of HCC. Evodiamine (Evo), one of the major bioactive components derived from fructus Evodiae, has long been shown to exert anti-hepatocellular carcinoma activity by suppressing activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK). In addition, in the Nucleotide-Binding Oligomerization Domain 1 (NOD1) pathway, NOD1 could initiate NF-κB-dependent and MAPK-dependent gene transcription. Recent experimental studies reported that the NOD1 pathway was related to controlling development of various tumors. Here we hypothesize that Evo exerts anti-hepatocellular carcinoma activity by inhibiting NOD1 to suppress NF-κB and MAPK activation. Therefore, we proved the anti-hepatocellular carcinoma activity of Evo on HCC cells and detected the effect of Evo on the NOD1 pathway. We found that Evo significantly induced cell cycle arrest at the G2/M phase, upregulated P53 and Bcl-2 associated X proteins (Bax) proteins, and downregulated B-cell lymphoma-2 (Bcl-2), cyclinB1, and cdc2 proteins in HCC cells. In addition, Evo reduced levels of NOD1, p-P65, p-ERK, p-p38, and p-JNK, where the level of IκBα of HCC cells increased. Furthermore, NOD1 agonist γ-D-Glu-mDAP (IE-DAP) treatment weakened the effect of Evo on suppression of NF-κB and MAPK activation and cellular proliferation of HCC. In an in vivo subcutaneous xenograft model, Evo also exhibited excellent tumor inhibitory effects via the NOD1 signal pathway. Our results demonstrate that Evo could induce apoptosis remarkably and the inhibitory effect of Evo on HCC cells may be through suppressing the NOD1 signal pathway in vitro and in vivo.
Highlights
With 854,000 incident cases diagnosed and 810,000 deaths globally in 2015, hepatocellular cancer (HCC) is the most common primary malignancy of the liver and is the third leading cause of cancer-related death worldwide [1,2]
To determine the function of Evo in controlling growth of HCC and the effect of Evo on the Nucleotide-Binding Oligomerization Domain 1 (NOD1) signal pathway, we proved the effect of Evo on proliferation of HCC cells and detected changes in the NOD1 pathway in vitro and in vivo
Our results demonstrate that Evo could induce apoptosis remarkably and the inhibitory effect of Evo on HCC cells may be through suppressing the NOD1 signal pathway in vitro and in vivo
Summary
With 854,000 incident cases diagnosed and 810,000 deaths globally in 2015, hepatocellular cancer (HCC) is the most common primary malignancy of the liver and is the third leading cause of cancer-related death worldwide [1,2]. It is characterized by high morbidity and mortality, high risk of intrahepatic recurrence, and poor prognosis [3,4,5]. This suppression by Evo on HCC has been known for several years [17], molecular details that underline this process are still being uncovered
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