Oridonin interrupts cellular bioenergetics to suppress glioma cell growth by down-regulating PCK2.

We aim to evaluate the tumor metabolic suppressive activity of Oridonin (extract of Rabdosia rubescens) in glioma and elucidate its potential mechanism. Effects of Oridonin on U251/U87 cells were determined by CCK8, RTCA, colony formation, flow cytometry, wound healing, and Transwell assay. Xenograft tumor model to evaluate the effect of Oridonin on glioma cells in vivo. Cellular bioenergetics were measured by Seahorse. RNA-seq was performed to screen potential biological pathways in Oridonin treated cells. Bioinformatics analysis of PCK2 in glioma was performed based on TCGA/CGGA. Endogenous PCK2 was knocked-down by lentivirus packaged shRNA. We found Oridonin significantly inhibited cell growth in U251/U87 in vitro and in vivo. Both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were decreased in Oridonin-treated U251/U87 cells. Oridonin treatment led to PCK2 down-regulation. Additionally, PCK2 was up-regulated in higher grade glioma and correlated with poor outcomes. Furthermore, PCK2 depletion significantly inhibited cell growth and decreased OCR/ECAR in U251/U87 which coincided with the effects of Oridonin. Therefore, we evaluated the potent anti-tumor property of Oridonin in glioma. Importantly, we demonstrated that PCK2 might be a novel target of Oridonin on glioma by inducing energy crisis and increasing oxidative stress.

Chlorogenic acid depresses cellular bioenergetics to suppress pancreatic carcinoma through modulating c-Myc-TFR1 axis.

Pancreatic ductal adenocarcinoma (PDAC) is severe malignant tumor in human, the outcomes of PDAC is extremely poor. Here, we evaluated the potential anti-tumor activity of chlorogenic Acid (CA) in PDAC. Here, we found CA was effective to suppress PDAC cell growth in vitro and in vivo. Importantly, we found overall oxygen consumption rate was significantly decreased in CA dose-dependent manner. We also found glycolysis reverse was decreased in CA-treated cells, while basal glycolysis and glycolytic capacity were not significantly changed. Mechanistically, we demonstrated TFR1 could be a novel downstream target of CA, which is essential for PDAC cell growth and cellular bioenergetics maintenance. Furthermore, we validated that CA-reduced c-Myc resulted to down-regulation of TFR1, which contributes to mitochondrial respiration dysfunction and cell growth delay. Together, this study indicates that CA suppresses PDAC cell growth through targeting c-Myc-TFR1 axis and suggests CA could be considered as a promising compound for PDAC treatment.

Epithelial and interstitial Notch1 activity contributes to the myofibroblastic phenotype and fibrosis.

BACKGROUND: Notch1 signalling is a stem-cell-related pathway that is essential for embryonic development, tissue regeneration and organogenesis. However, the role of Notch1 in the formation of myofibroblasts and fibrosis in kidneys following injury remains unknown. METHODS: The activity of Notch1 signalling was evaluated in fibrotic kidneys in CKD patients and in ureteral obstructive models in vivo and in cultured fibroblasts and TECs in vitro. In addition, the crosstalk of Notch1 with TGF-ß1/Smad2/3 signalling was also investigated. RESULTS: Notch1 activity was elevated in fibrotic kidneys of rat models and patients with chronic kidney disease (CKD). Further study revealed that epithelial and interstitial Notch1 activity correlated with an α-SMA-positive myofibroblastic phenotype. In vitro, injury stimulated epithelial Notch1 activation and epithelial-mesenchymal transition (EMT), resulting in matrix deposition in tubular epithelial cells (TECs). Additionally, interstitial Notch1 activation in association with fibroblast-myofibroblast differentiation (FMD) in fibroblasts mediated a myofibroblastic phenotype. These TGF-ß1/Smad2/3-dependent phenotypic transitions were abolished by Notch1 knockdown or a specific antagonist, DAPT, and were exacerbated by Notch1 overexpression or an activator Jagged-1-Fc chimaera protein. Interestingly, as a major driving force behind the EMT and FMD, TGF-ß1, also induced epithelial and interstitial Notch1 activity, indicating that TGF-ß1 may engage in crosstalk with Notch1 signalling to trigger fibrogenesis. CONCLUSION: These findings suggest that epithelial and interstitial Notch1 activation in kidneys following injury contributes to the myofibroblastic phenotype and fibrosis through the EMT in TECs and to the FMD in fibroblasts by targeting downstream TGF-ß1/Smad2/3 signalling.

Fraxetin Inhibits the Proliferation and Metastasis of Glioma Cells by Inactivating JAK2/STAT3 Signaling.

Glioma is the most common brain tumor and is characterized by high mortality rates, high recurrence rates, and short survival time. Migration and invasion are the basic features of gliomas. Thus, inhibition of migration and invasion may be beneficial for the treatment of patients with glioma. Due to its antitumor activity and chemical reactivity, fraxetin has attracted extensive interest and has been proven to be an effective antitumor agent in various cancer types. However, currently, the potential effects of fraxetin on glioma have not been investigated. Here, we demonstrate that fraxetin can inhibit the proliferation, invasion, and migration of glioma and induce apoptosis of glioma cells in vitro and in vivo. Therefore, these findings establish fraxetin as a drug candidate for glioma treatment. Furthermore, fraxetin was able to effectively inhibit the JAK2/STAT3 signaling in glioma. In summary, our results show that fraxetin inhibits proliferation, invasion, and migration of glioma by inhibiting JAK2/STAT3 signaling and inducing apoptosis of glioma cells. The present study provides a solid basis for the development of new glioma therapies.

Development and validation of a ferroptosis-related model for three digestive tract tumors based on a pan-cancer analysis.

Aims: To develop a ferroptosis gene-based survival-predictor model for predicting the prognosis of patients with digestive tract tumors, a pan-caner analysis was performed. Materials & methods: Based on unsupervised clustering and the expression levels of ferroptosis genes, patients with cancer were divided into two clusters. The least absolute shrinkage and selection operator method Cox regression analysis was used to establish the survival-predictor model. Results: Based on the pan-cancer analysis, a 20 gene-based survival-predictor model for predicting survival rates was developed, which was validated in patients with hepatocellular carcinoma. Conclusion: The survival-predictor model accurately predicted the prognosis of patients with digestive tract tumors.