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Colorectal cancer (CRC), the third most frequent occurred cancer, is associated with high mortality and extremely poor prognosis. Ginsenoside Rg3 (Rg3), one of the pharmacologically active components of traditional Chinese herbal medicine Panax ginseng , exerts antitumor effects against several types of cancer growth, including colorectal cancer. However, the detailed molecular mechanisms and particularly the signaling pathways that are decisive in this process are not yet fully elucidated. The present study was carried out to determine the antitumor effects of Rg3 using human colorectal cells in vitro and Xenograft tumor model of human colon cancer in vivo. We found that Rg3 effectively suppressed the proliferation of cancer cells in three human colorectal cancer cell lines (HCT116, HT29, SW480). In addition, intraperitoneal injection of Rg3 for 3 weeks significantly inhibited the growth of xenografts in nude mice. Furthermore, we determined the potential underlying mechanisms for these actions. Treatment with Rg3 significantly inhibited the transactivation of C/EBPβ and NF-κB, as well as the association of C/EBPβ with p65-NFκB in nucleus. However, when SW-480 cells were co-transfected with C/EBPβ, or pretreatment with TNFα, Rg3 failed to inhibit tumor growth. Taken together, our results revealed a robust anti-tumor effect of Rg3, which is mediated by inhibition of C/EBPβ/NF-κB signaling. [ABSTRACT FROM AUTHOR]

Highlights • IL-2 promotes sorafenib-mediated apoptosis in Huh7 cells. • IL-2 in combination with sorafenib interrupts mitochondrial metabolism. • Mitochondrial fragmentation is augmented by IL-2 in the presence of sorafenib. Abstract Sorafenib is a standard targeted drug used to treat hepatocellular carcinoma (HCC). Notably, cytokine has been found to further enhance the therapeutic effectiveness of the targeted drug. Thereby, the aim of this study is to verify whether cytokine IL-2 could increase the anti-cancer effects of sorafenib on liver cancer in vitro. Huh7 cells were used in the present study and the cell apoptosis and migration were determined in response to sorafenib treatment. Then, siRNA and pathway blocker were used to determine the molecular mechanisms by which IL-2 enhance the therapeutic effectiveness of Huh7 liver cancer cell in vitro. The data in our study illustrated that sorafenib treatment induced apoptosis in Huh7 liver cancer cell in vitro, an effect that was accompanied with a drop in cell proliferation and migration. Biological investigation demonstrated that IL-2 supplementation further augmented the pro-apoptotic effects of sorafenib in vitro. At the molecular levels, the combination of IL-2 and sorafenib impaired mitochondrial respiratory function, reduced mitochondrial potential, promoted mitochondrial ROS overloading and activated mitochondrial apoptotic pathway. Meanwhile, we found that IL-2 supplementation induced mitochondrial stress via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. Blockade of the JNK signalling pathway and/or knockdown of TAZ could abrogate the inhibitor effects of IL-2/sorafenib on liver cancer survival, growth and mobility. Collectively, these data indicated that IL-2 supplementation could further augment the anti-cancer effectiveness of sorafenib via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. This finding identifies mitochondrial stress and the JNK-Hippo pathway as the potential targets to treat liver cancer. [ABSTRACT FROM AUTHOR]

Large tumor suppressor 2 (LATS2), an important mediator of the cell apoptotic response pathway, has been linked to the progression of several cancers. Here, we described the molecular feature of LATS2 as a novel antitumor factor in liver cancer cells in vitro. Western blotting was used to detect the expression of LATS2 and its downstream factors. ELISA, immunofluorescence, and flow cytometry were used to evaluate the alterations of mitochondrial function in response to LATS2 overexpression. Adenovirus-loaded LATS2 and siRNA against DRP1 were transfected into liver cancer cells to overexpress LATS2 and knockdown DRP1 expression, respectively. The results of the present study demonstrated that overexpression of LATS2 was closely associated with more liver cancer cell death. Mechanistically, LATS2 overexpression increased the expression of DRP1, and DRP1 elevated mitochondrial division, an effect that was accompanied by mitochondrial dysfunction, including mitochondrial membrane potential reduction, mitochondrial respiratory complex downregulation, mitochondrial cyt-c release into the nucleus and mitochondrial oxidative injury. Moreover, LATS2 overexpression also initiated mitochondrial apoptosis, and this process was highly dependent on DRP1-related mitochondrial division. Molecular investigations demonstrated that LATS2 modulated DRP1 expression via the Wnt/β-catenin pathway. Inhibition of the Wnt/β-catenin pathway pregented LATS2-mediated DRP1 upregulation, ultimately sustaining mitochondrial function and cell viability in the presence of LATS2 overexpression. Altogether, the above data identify LATS2-Wnt/β-catenin/DRP1/mitochondrial division as a novel anticancer signaling pathway promoting cancer cell death, which might be an attractive therapeutic target for the treatment of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]