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Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related deaths worldwide. Overexpression of pleomorphic adenoma gene like‐2 (PLAGL2) is associated with tumorigenesis. However, its function in HCC is unclear, and there are currently no anti‐HCC drugs that target PLAGL2. Drug repositioning may facilitate the development of PLAGL2‐targeted drug candidates. Methods: The expression of PLAGL2 in HCC clinical tissue samples and HCC cell lines was analyzed by western blotting. The constructed HCC cell models were used to confirm the underlying function of PLAGL2 as a therapeutic target. Multiple in vitro and in vivo assays were conducted to determine the anti‐proliferative and apoptosis‐inducing effects of selenium sulfide (SeS2), which is clinically used for the treatment of seborrheic dermatitis and tinea versicolor. Results: PLAGL2 expression was higher in HCC tumor tissues than in normal adjacent tissues. Its overexpression promoted the resistance of HCC cells of mitochondrial apoptosis through the regulation of the downstream C‐MET/STAT3 signaling axis. SeS2 exerted significant anti‐proliferative and apoptosis‐inducing effects on HCC cells in a PLAGL2‐dependent manner. Mechanistically, SeS2 suppressed C‐MET/STAT3, AKT/mTOR, and MAPK signaling and triggered Bcl‐2/Cyto C/Caspase‐mediated intrinsic mitochondrial apoptosis both in vitro and in vivo. Conclusions: Our data reveal an important role of PLAGL2 in apoptosis resistance in HCC and highlight the potential of using SeS2 as a PLAGL2 inhibitor in patients with HCC. [ABSTRACT FROM AUTHOR]

Both PI3K/AKT/mTOR and mitogen activated protein kinase (MAPK) signaling cascades played an important role in tumorigenesis, a more complete understanding of these signaling pathways allowed the development of new therapeutic strategies. Total saponins isolated from Radix et Rhizoma Leonticis (RLTS) was recognized with anticancer properties. In a murine hepatocellular carcinoma H22 cell-bearing mouse model, RLTS exhibited significant inhibitory effect on tumor growth. Here, we investigated the role of RLTS on the PI3K/AKT/mTOR signaling pathway and MAPK pathways in liver and lung cancer cells. Results obtained showed RLTS inhibited cell proliferation and induced cell apoptosis in vitro , which attributed to the inhibition on the activation of PI3K/AKT/mTOR cascade and its related signaling molecules, such as activated VEGFR and NF-κB, and activation of p38 MAPK in tumor cells. Additional, RLTS inhibited cell migration and downregulated proteins that mediated metastasis including CXCR4, MMP2 and MMP9. Overall, these findings suggested that RLTS interfered with multiple signaling cascades involved in tumorigenesis and had potential in cancer therapy. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Loss of WW-domain containing oxidoreductase (WWOX) has been proven to be associated with malignant metastasis in patients with HCC. In this study, by using a non-biased CRISPR knockout genetic screen targeting 19,050 human genes, we found that toosendanin (TSN) is a novel druggable WWOX candidate agonist for metastatic HCC patients. We also found that TSN exhibited significant anti-proliferative and anti-metastatic effects on HCC cells in a WWOX-dependent manner. Overexpression and knockdown of WWOX in vitro and in vivo confirmed that the suppression of HCC by TSN involved WWOX. TSN regulated Stat3, DVL2, and GSK3β by transforming their interactions with WWOX as demonstrated by a Co-IP assay. TSN accelerated the degradation of β-catenin by promoting the function of APC, AXIN1, CK1, and GSK3β complex. Nuclear translocation of p-Stat3 Y705 and β-catenin was impeded by the TSN-induced blockade of JAK2/Stat3 and Wnt/β-catenin signaling, accompanied by the inhibition of MMPs and C-MYC. [ABSTRACT FROM AUTHOR]

Abstract: In order to investigate the anti-angiogenesis potential and related mechanisms of Ta1722 (a novel taspine derivative compound), a series of experiments in vivo and in vitro were carried out. The proliferation on human cell lines of SMMC-7721, A549, MCF-7, Lovo, and ECV304 was examined by MTT. Angiogenesis inhibition was examined by chick embryo chorioallantoic membrane (CAM) angiogenesis and tube formation assays. Related angiogenesis proteins and their mRNA expression were determined by western blotting and RT-PCR. In addition, the SMMC-7721 nude mouse xenotransplant model was used to evaluate the inhibition of tumor growth. The results showed that Ta1722 inhibited cell proliferation, angiogenesis of CAM and tube formation, and downregulated related positive angiogenesis proteins. The above indicated Ta1722 could serve as a promising candidate of angiogenesis inhibitors by interrupting the VEGF/VEGFR-2 pathway. [Copyright &y& Elsevier]

Cantharidin suppressed HCC cell growth and induced intrinsic cell apoptosis by targeting EphB4, which inhibited a novel target, the downstream JAK2/STAT3 pathway, and the previously known target, the PI3K/Akt signaling. • EphB4 was significantly up-regulated in HCC tumors and could be an effective target for HCC therapy. • JAK2/STAT3 was identified as novel downstream targets of EphB4. • Cantharidin (CTD) showed good suppression on HCC cell growth by targeting EphB4. • CTD induced intrinsic apoptosis by regulating the Bcl-2/Cyto-C/Caspase signaling pathway. • CTD inhibited EphB4 downstream JAK2/STAT3 and PI3K/Akt signaling events. Hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. The tyrosine kinase receptor EphB4 promotes oncogenesis and tumor development and progression. Its inhibition is regarded as an effective strategy for the treatment of solid tumors. In the present study, we identified cantharidin as a novel EphB4 inhibitor for HCC treatment and evaluated the underlying molecular pharmacological mechanisms of action. We observed increased expression levels of EphB4 in HCC patients and a positive correlation between EphB4 and p-JAK2 levels in HCC patient samples. Knockdown of EphB4 using small interfering RNA decreased the expression levels of p-JAK2 and p-STAT3 in HCC cells, suggesting JAK2/STAT3 being a novel downstream signaling target of EphB4. Cell viability experiments revealed that the anti-cancer effect of cantharidin was positively correlated with EphB4 expression levels in HCC cell lines. We confirmed the potent antiproliferative activity of cantharidin on HepG2 cells with high expression of EphB4 and tumor xenograft. Molecular docking assay, immunoblotting assay and quantitative reverse transcription PCR assay indicated that cantharidin bound to EphB4, and thereby resulted in EphB4 suppression at mRNA and protein levels. Hep3B and SMMC-7721 cells were with low expression of EphB4. In EphB4−/HepG2, EphB4+/HepG2, and EphB4+/Hep3B cells, EphB4 knockdown alleviated the cantharidin-induced decrease in cell viability and colony formation ability and increase in apoptosis in HepG2 cells, while its overexpression exacerbated these effects in Hep3B cells and increased the apoptosis of HepG2 cells. In nude mouse models, cantharidin suppressed tumor growth more effectively in EphB4+/SMMC-7721 xenografts than in wild-type SMMC-7721 xenografts. Underlying mechanistic study showed that by targeting EphB4, cantharidin blocked a novel target, the downstream JAK2/STAT3 pathway, and the previously known target, the PI3K/Akt signaling, resulting in intrinsic apoptosis. These results indicated that cantharidin may be a potential candidate for HCC treatment by regulating the EphB4 signaling pathway. [ABSTRACT FROM AUTHOR]