27-Hydroxycholesterol is a specific factor in the neoplastic microenvironment of HCC that causes MDR via GRP75 regulation of the redox balance and metabolic reprogramming.

OBJECTIVE: Due to the tissue specificity of the liver, long-term exposure to a high concentration of 27-hydroxycholesterol (27HC) is a special characteristic of the tumour microenvironment in hepatocellular carcinoma (HCC). However, what occurs after HCC cells are long-term exposure to 27HC and the molecular mechanisms involved remain largely unexamined. METHODS: A long-term 27HC-treated HepG2 cell line and the xenografts in nude mice were used as experimental models. Molecular mechanisms were investigated using bioinformatics analysis and molecular biological experiments. RESULTS: Here, we found that by inducing an increase in oxidative stress signalling, 27HC activated glucose-regulated protein 75 (GRP75). On the one hand, GRP75 resulted in a change in the redox balance by regulating ROS generation and antioxidant system activity via affecting MMP, NRF2, HO-1, and NQO1 levels. On the other hand, GRP75 modified the metabolic reprogramming process by regulating key factors (HIF-1α, p-Akt, and c-myc) and glucose uptake, facilitating HCC cell growth in the inhospitable microenvironment. These two factors caused HCC cells to resist 27HC-induced cytotoxicity and attain multidrug resistance (MDR). CONCLUSIONS: Our present study not only identified 27HC, a characteristic component of the neoplastic microenvironment of HCC that causes MDR via GRP75 to regulate the redox balance and metabolic reprogramming, but also revealed that targeted intervention by the "switch"-like molecule GRP75 could reverse the effect of 27HC from cancer promotion to cytotoxicity in HCC, suggesting a new strategy for specific intervention of HCC.

Sinomenine attenuated dextran sulfate sodium-induced inflammatory responses by promoting 14-3-3θ protein and inhibiting NF-κB signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: The rhizome of Chinese medical plant QingTeng (scientific name: Sinomenium acutum (Thunb.) Rehd. et Wils.) is widely used by traditional medical doctors for anti-inflammation and immunoregulatory in China and other Asian countries. AIM OF THE STUDY: The purpose of this study was to evaluate the effects and possible mechanisms of sinomenine resistance against DSS-induced inflammation in vitro and in vivo. MATERIALS AND METHODS: The UC model was induced by treating female mice with 3% DSS in vivo and human colonic epithelial cells (Hcoepic) with 0.8 mg/ml DSS in vitro. The mice and Hcoepic were then treated with sinomenine. Inflammatory factors were detected using ELISA and qRT-PCR. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 and 14-3-3θ were analyzed by bioinformatic analysis and verified by western blotting, immunofluorescent staining or immunohistochemistry. RESULTS: DSS-induced Hcoepic underwent high inflammation and oxidative stress conditions, whereas sinomenine reduced the uncontrolled immune microenvironment by suppressing NF-κB signaling and targeting 14-3-3θ. Knockdown of 14-3-3θ decreased the protective effect of sinomenine against DSS-induced inflammation in vitro. Moreover, sinomenine promoted 14-3-3θ protein expression and inhibited NF-κB p65 signaling in DSS-induced mice. CONCLUSION: These findings suggest that 14-3-3θ plays an important role in sinomenine against DSS treatment, and sinomenine could be considered a potential drug for the treatment of UC.

Arsenic trioxide enhances the chemotherapeutic efficiency of cisplatin in cholangiocarcinoma cells via inhibiting the 14-3-3ε-mediated survival mechanism.

Cholangiocarcinoma (CCA) is the second most frequent primary liver carcinoma with high degrees of malignancy and mortality. Chemotherapy plays a key role in the treatment of CCA, however, the low chemotherapeutic efficiency leads to a bottleneck. So unraveling the potential mechanisms to enhance the efficiency (reduced the dosage and enhanced the effects of chemotherapy drugs) and identifying alternative therapeutic strategies in CCA are urgently needed. Here, we found that, in CCA cells, when cisplatin (CDDP) displayed anti-tumor effects, it activated 14-3-3ε simultaneously, which in turn formed a survival mechanism via the phosphorylation of phosphatidylinositol 3-kinase/protein kinase B (PI-3K/Akt). However, low concentrations of arsenic trioxide (ATO) could disrupt such survival mechanism and enhanced the efficiency. For the molecular mechanisms, ATO attenuated 14-3-3ε at both transcriptional and post-transcriptional (ubiquitination degradation) levels. Such repressive effect blocked the activation of PI-3K/Akt, and its downstream anti-apoptotic factors, B-cell lymphoma 2 (Bcl-2), and survivin. Collectively, our present study revealed that the synergistic effects of ATO and CDDP could be a novel approach for enhancing the efficiency, which provides an innovative therapeutic vision for the treatment of CCA.