Abstract
Liver cancer, also known as primary liver cancer, is cancer that starts in the liver. JNU-144, a new meroterpenoid purified from Lithospermum erythrorhizon, has exhibited promising anticancer activity; however, the molecular mechanisms of action of JNU-144 on malignant cells remain unclear. Our studies revealed that JNU-144 suppressed cell viability and proliferation in hepatoma cells by downregulating mTOR activation. Meanwhile, JNU-144 activated the intrinsic apoptosis pathway and subsequently triggered apoptotic cell death in SMMC-7721 cells. We also found that JNU-144 inhibited the epithelial–mesenchymal transition in both SMMC-7721 and HepG2 cells through reprogramming of epithelial–mesenchymal transition (EMT)-related gene expression or regulating protein instability. These findings indicate that JNU-144 exerts potent anticancer activity in hepatoma cells and may be developed as a potential therapeutic drug.
Highlights
Cancer that begins in the liver is referred to as primary liver cancer[1]
We found that JNU-144 inhibited epithelial–mesenchymal transition (EMT) in both SMMC-7721 and HepG2 cells by reprogramming the gene expression profile
We found that JNU-144 treatment inhibited ERK1/2 activation in a dose- and time-dependent manner (Fig. 1g,h and S1e,f). These findings were in accordance with a number of recent studies that have reported AKT independent regulation of mammalian target of rapamycin (mTOR) signaling by the ERK/MAPK pathway[20], which suggested that JNU-144 induced mTOR inhibition may be mediated by MEK/ERK pathway
Summary
Cancer that begins in the liver is referred to as primary liver cancer[1]. Correspondingly, cancer that spreads from other tissues to the liver is known as liver metastasis, which is much more common[2]. Hepatocellular carcinoma (HCC), formed by malignant hepatocytes, accounts for approximately 75% of all cases of primary liver cancer[3]. As of 2010, primary liver cancer resulted in 754,000 deaths globally, making it the third-most lethal form of cancer[5]. As EMT plays a crucial role in cell differentiation and metastasis in cancer progression, it is tightly regulated through cooperation and crosstalk between signaling pathways in vivo[10,11]. With the increased understanding of the regulatory networks defining EMT, the search for specific inhibitors of tumor metastasis has become even more promising. These results suggest potential for JNU-144 as a novel therapeutic drug for liver cancer
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