Norcantharidin inhibits IL-6-induced epithelial-mesenchymal transition via the JAK2/STAT3/TWIST signaling pathway in hepatocellular carcinoma cells

Abstract

Epithelial-mesenchymal transition (EMT), plays a vital role in hepatocellular carcinoma (HCC) development and metastasis. Norcantharidin (NCTD; 7-oxabicyclo (2.2.1) heptane-2,3-dicarboxylic anhydride) plays anticancer roles in the regulation of tumor cell proliferation, apoptosis and migration. However, the molecular mechanism of HCC EMT and the effects of NCTD in the HCC EMT process have been either poorly elucidated or not studied. In this study, HCC EMT was induced by the treatment of IL-6 and various concentrations of NCTD (0, 30, 60 and 120 µM) were treated with HCC cell lines, HCCLM3 and SMMC-7721. We investigated the effect of NCTD on the invasion of HCC cells by using Transwell assay. Immunofluorescence staining, western blot analysis and quantitative RT-PCR were performed to evaluate the protein and mRNA expression levels of HCC cells. Here, using cell line models, our data demonstrated that interleukin 6 (IL-6) induced EMT through the JAK/STAT3/TWIST pathway in HCC. Moreover, our studies revealed that NCTD markedly inhibited IL-6-induced EMT and cell invasiveness. Signaling studies revealed that NCTD sufficiently suppressed JAK/STAT3/TWIST signaling to reverse the IL-6-promoting effects. Collectively, these data provide evidence for the use of NCTD as a potential anticancer drug in HCC metastatic patients.

Cantharidic acid induces apoptosis through the p38 MAPK signaling pathway in human hepatocellular carcinoma

“…Le et al reported that cantharidin induces apoptosis in HCC stem cells . Moreover, numerous studies have shown NCTD, a cantharidin analog, exhibits anticancer activities, including apoptosis, antiproliferative activity, and antimetastatic activity in the HCC cell lines . Our previous study also showed that, compared with the IC50 (21 μM) of cantharidin, anhydride‐modified cantharidin analogs exhibited low cytotoxicity (IC50 > 200 μM) in primary cultured rat hepatocytes .…”

“…17 Moreover, numerous studies have shown NCTD, a cantharidin analog, exhibits anticancer activities, including apoptosis, antiproliferative activity, and antimetastatic activity in the HCC cell lines. [18][19][20][21] Our previous study also showed that, compared with the IC50 (21 lM) of cantharidin, anhydride-modified cantharidin analogs exhibited low cytotoxicity (IC50 > 200 lM) in primary cultured rat hepatocytes. 15 CA is a hydrolysis product of cantharidin and is a cantharidin analog; it exhibits more hydrophilic ability and bioavailability than other cantharidin analogs.…”

Compound K Induces Endoplasmic Reticulum Stress and Apoptosis in Human Liver Cancer Cells by Regulating STAT3

“…HCC is the fifth most commonly diagnosed cancer and the second leading cause of cancer-related mortality worldwide [ 28 , 29 ]. Because of late diagnosis and the limited number of effective drugs, HCC has a poor prognosis.…”

Insight into norcantharidin, a small-molecule synthetic compound with potential multi-target anticancer activities

“…Furthermore, epithelial-mesenchymal transition (EMT) is widely involved in the invasion and metastasis of malignant epithelial tumors [79]. NCTD inhibits the EMT process in non-small cell lung cancer, colorectal cancer and hepatocellular cancer cells via the αvβ6-ERK-Ets1 (E-Twenty-Six-1) signaling pathway blocking and NCTDmediated Yes-associated protein (YAP) inhibition [78,80,81]. These regulatory mechanism of NCTD against tumor invasion and metastasis is detailed in Fig.…”