PGAM4 silencing inhibited glycolysis and chemoresistance to temozolomide in glioma cells.

Gliomas account for about 80% of malignant brain tumors. The incidence of a new brain tumor is 6.4 per 100,000 persons per year with an overall 5-year survival rate of 33.4%. Regardless of the great advances that have been made in recent years, the causes and pathogenesis of glioma remain unclear. Here we study how phosphoglycerate mutase 4 (PGAM4) contributes to glioma. Using a variety of methods to examine glioma cell viability, proliferation, apoptosis, glycolysis, as well as ChIP coanalysis with modified histone H3, we showed that PGAM4 was significantly upregulated in patients with glioma and associated with poor survival. Silencing PGAM4 attenuated cell viability, proliferation, and glycolysis in T98G cells and suppressed tumor growth in vivo, while overexpressing PGAM4 promoted cell viability, proliferation, and glycolysis in U251 cells via regulating glycolysis pathway. Study also revealed that PGAM4 was regulated by EP300-mediated modifications of H3K27ac. PGAM4 silencing inhibited cell viability and proliferation, suppressed tumor growth, and decreased chemoresistance to temozolomide in glioma cells through suppressing glycolysis.

CCL2 activates AKT signaling to promote glycolysis and chemoresistance in glioma cells.

The incidence of gliomas is increasing. Although great progress in glioma treatment has been made, the clinical outcome remains unsatisfactory. Chemokine (C-C motif) ligand 2 (CCL2) plays a key role in different types of cancers, including glioma. However, the function of CCL2 in glioma chemoresistance is not fully understood. In the current study, CCL2 was significantly upregulated in glioma. More importantly, CCL2 and CCR2 were significantly upregulated in temozolomide (TMZ)-resistant glioma. TMZ-resistant malignant glioblastoma cells (U251/TMZ) had higher expressions of CCL2 and CCR2 and a higher level of glycolysis as compared to its parental cell line U251. Silencing of CCL2 in U251/TMZ cells inhibited glycolysis. Overexpression of CCL2 reduced TMZ-induced apoptosis through activation of the AKT pathway and promotion of glycolysis. Moreover, overexpression of CCL2 significantly reduced the antitumor effect of TMZ in vivo. In conclusion, CCL2 overexpression reduced the antitumor effect of TMZ by enhancing glycolysis through activation of AKT signaling. The findings highlighted the importance of CCL2/CCR2/glycolysis and its potential value in developing new treatment for glioma.

Valtrate as a novel therapeutic agent exhibits potent anti-pancreatic cancer activity by inhibiting Stat3 signaling.

BACKGROUND: Valtrate is a novel epoxy iridoid ester isolated from Chinese herbal medicine Valeriana jatamansi Jones with anti-proliferative activity against various human cancer cell lines. However, its efficacy and molecular mechanisms against pancreatic cancer (PC) cells are largely unclear. PURPOSE: To investigate the anti-cancer effects of valtrate on PC cell lines and its underlying mechanisms. METHODS: MTT assay was first performed to detect the effect of valtrate on cell viability in human PC cell lines and normal pancreatic epithelial cells HPDE. Cell apoptosis and cycle phase assay were detected by flow cytometry. The relative mRNA expressions of Bax, Bcl-2, c-Myc, and CyclinB1 were tested by quantitative PCR (qPCR) assay. The expression of relative proteins was detected by Western blotting (WB). A PANC-1luc cells xenograft mouse model in nu/nu female mice was used to elucidate the effect of valtrate on tumor growth in vivo. RESULTS: Valtrate significantly inhibited the growth of PC cells without affecting the growth of normal pancreatic epithelial cells HPDE, induced significant apoptosis and cell cycle arrest in G2/M phase. Moreover, valtrate inhibited the tumor growth of PC cell PANC-1 in xenograft mice by 61%. Further mechanism study demonstrated that valtrate could increase the expression level of Bax, suppress Bcl-2 as well as c-Myc and Cyclin B1, inhibit the transcriptional activity of Stat3, while valtrate decreased the expression level of Stat3 and phosphated-Stat3 (Tyr705) and induced the high molecular aggregation of Stat3. Molecular docking analysis predicted that valtrate might interact with Cys712 of Stat3 protein. Valtrate could also induce a transient depleted intracellular glutathione (GSH) level and increased reactive oxygen species (ROS). NAC (N-acetylcysteine), a reducer reversed valtrate-induced the depletion of Stat3, p-Stat3, c-Myc, and Cyclin B1. CONCLUSION: Valtrate exerts anti-cancer activity against PC cells by directly targeting Stat3 through a covalent linkage to inhibit Stat3 activity, which causes apoptosis and cell cycle arrest.

Association of body mass index, waist circumference, and metabolic syndrome with serum cystatin C in a Chinese population.

BACKGROUND: The aim of the study was to evaluate the association of body mass index (BMI), waist circumference (WC), and metabolic syndrome (MetS) with serum cystatin C (CysC) in a Chinese population. METHODS: The population was composed of 5866 subjects. MetS was diagnosed using the American Heart Association/National Heart, Lung, and Blood Institute 2005 (NCEP-R) criteria. Covariates were analyzed using logistic regression and Spearman partial correlation. RESULTS: In this population, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), high sensitivity C-reactive protein (hs-CRP), BMI, WC, systolic blood pressure (SBP), diastolic blood pressure (DBP), serum creatinine (Scr), and CysC were significantly higher, and HDL-C and the estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration) (eGFRCKD-EPI) were significantly lower in the MetS than in the non-MetS group. TG, LDL-C, FPG, hs-CRP, BMI, WC, SBP, DBP, and Scr were significantly higher, and HDL-C and eGFRCKD-EPI were significantly lower in the 4th quartile than in the 1st quartile of CysC. Logistic regression analysis showed that sex, age, hs-CRP, and CysC were independently associated with the presence of MetS (OR = 3.732, 1.028, 1.051, and 3.334, respectively; P < 0.05). No significant association between the presence of MetS and either Scr or eGFRCKD-EPI was observed. After adjustment for age and sex, BMI, WC, hs-CRP, and Scr were all positively correlated, whereas eGFRCKD-EPI was negatively correlated with CysC (r = 0.029, 0.061, 0.189, 0.227, and -0.210, respectively; P < 0.05). CONCLUSION: The present study revealed that the CysC was more closely associated with the presence of MetS, as compared Scr or eGFRCKD-EPI. CysC was positively correlated with BMI, and more strongly, positively correlated with WC and inflammation.

Coix seed emulsion synergistically enhances the antitumor activity of gemcitabine in pancreatic cancer through abrogation of NF-κB signaling.

Clinical outcomes in patients with pancreatic cancer (PC) continue to be dismal, in part due to de novo and acquired chemoresistance. In the present study, we provide preclinical evidence that pre-treatment with coix seed emulsion, an injectable agent extracted from coix seeds, synergistically sensitized PC cell lines (BxPC-3, PANC-1 and AsPC-1) to gemcitabine, both in vitro and in vivo. Such pretreatment led to significant induction of pro-apoptosis proteins, including caspase-3, cleaved-PARP and Bax (P<0.05), after lower doses of gemcitabine compared to monotherapy. We also showed that coix seed emulsion suppressed the constitutive and gemcitabine-induced activation of nuclear factor-κB (NF-κB), as shown with the use of electrophoretic mobility shift, reporter and immunoblotting analyses. Coix seed emulsion pretreatment also downregulated the NF-κB-dependent anti­apoptotic molecules Bcl-2, survivin and cyclooxygenase-2. In vivo, coix seed emulsion combined with gemcitabine had a much greater antitumor effect than the effect of either agent alone, consistent with the downregulation of the proliferation index, and the results of immunostaining for Ki-67, or for the NF-κB subunit p65. Overall, our data demonstrated that coix seed emulsion abrogated gemcitabine-induced activation of NF-κB, and synergistically sensitized PC cells to gemcitabine therapy.