Reprogramming of arachidonate metabolism confers temozolomide resistance to glioblastoma through enhancing mitochondrial activity in fatty acid oxidation.

BACKGROUND: Sp1 is involved in the recurrence of glioblastoma (GBM) due to the acquirement of resistance to temozolomide (TMZ). Particularly, the role of Sp1 in metabolic reprogramming for drug resistance remains unknown. METHODS: RNA-Seq and mass spectrometry were used to analyze gene expression and metabolites amounts in paired GBM specimens (primary vs. recurrent) and in paired GBM cells (sensitive vs. resistant). ω-3/6 fatty acid and arachidonic acid (AA) metabolism in GBM patients were analyzed by targeted metabolome. Mitochondrial functions were determined by Seahorse XF Mito Stress Test, RNA-Seq, metabolome and substrate utilization for producing ATP. Therapeutic options targeting prostaglandin (PG) E2 in TMZ-resistant GBM were validated in vitro and in vivo. RESULTS: Among the metabolic pathways, Sp1 increased the prostaglandin-endoperoxide synthase 2 expression and PGE2 production in TMZ-resistant GBM. Mitochondrial genes and metabolites were obviously increased by PGE2, and these characteristics were required for developing resistance in GBM cells. For inducing TMZ resistance, PGE2 activated mitochondrial functions, including fatty acid ß-oxidation (FAO) and tricarboxylic acid (TCA) cycle progression, through PGE2 receptors, E-type prostanoid (EP)1 and EP3. Additionally, EP1 antagonist ONO-8713 inhibited the survival of TMZ-resistant GBM synergistically with TMZ. CONCLUSION: Sp1-regulated PGE2 production activates FAO and TCA cycle in mitochondria, through EP1 and EP3 receptors, resulting in TMZ resistance in GBM. These results will provide us a new strategy to attenuate drug resistance or to re-sensitize recurred GBM.

Comprehensive analysis of temozolomide treatment for patients with glioma.

BACKGROUND: This analysis was conducted to evaluate the efficacy and safety of temozolomide based chemotherapy in treating patients with glioma. METHODS: Clinical studies evaluating the efficacy and safety of temozolomide based regimens for patients with glioma were identified using a predefined search strategy. Pooled response rates (RRs) were calculated. RESULTS: In temozolomide based regimens, 5 clinical studies including 152 patients with advanced glioma were considered eligible for inclusion. Four clinical studies included temozolomide. Systematic analysis suggested that, in all patients, pooled CR was 21% (32/152) , and PR was 21% (32/152). Grade 3/4 toxicity included neutropenia, thrombocytopenia, and anemia. No grade 3 or 4 renal or liver toxicity was observed. No treatment related death occurred with temozolomide based treatment. CONCLUSION: This systematic analysis suggests that temozolomide based regimens are associated with mild response rate and acceptable toxicity for treatment of glioma patients.

Correlations of MUC15 overexpression with clinicopathological features and prognosis of glioma.

The abnormal expression of MUC15, a novel cell membrane-associated mucin, has been reported to predict poor survival in several cancers. The aim of the present study was to examine the expression of MUC15 in glioma and its correlation with clinicopathological features, including the survival of patients with glioma. The mRNA expression level of MUC15 was determined by RT-PCR, quantitative RT-PCR (RT-qPCR) and Western blotting in seven normal brain tissues and seven glioma tissues, respectively. The protein expression level of MUC15 was immunohistochemically detected in paraffin-embedded samples of 317 glioma tissues and 115 noncancerous brain tissues. The association of MUC15 expression levels with the clinicopathologic features and the prognosis was analyzed. The results showed that both mRNA and protein levels of MUC15 were significantly increased in glioma as compared with those in noncancerous brain tissue. Moreover, MUC15 overexpression was positively correlated with the advanced clinical stages of glioam patients (P<0.01). Furthermore, MUC15 expression levels were significantly correlated with the progression of glioma (P<0.001). Survival analysis indicated that glioma patients with higher MUC15 expression had a significantly shorter overall and 5-year survival time than those with low MUC15 expression. Multivariate analysis suggested that MUC15 overexpression was an independent factor for prognosis (hazard risk: 3.216; P=0.009). It was concluded that MUC15 is overexpressed in glioma tissues. Its overexpression correlates with tumor progression and it is a potentially unfavorable prognostic factor for patients with glioma.

Study of the expression levels of Hepatocyte nuclear factor 4 alpha and 3 beta in patients with different outcome of HBV infection.

Hepatocyte nuclear factors 4 alpha (HNF4α) and 3 beta (HNF3ß) are members of a group of liver-enriched transcription factors (LETFs) that play important roles in regulating the replication of hepatitis B virus (HBV) and liver inflammation. However, the relationship of the level of HNF4α and HNF3ß with the severity of HBV-infected liver diseases is unclear. In this study, liver tissue samples from different types of HBV patients were collected, and HNF4α and HNF3ß expression were detected by immunohistochemistry. The expression of HNF4α was significant higher in patients with severe hepatitis B(SHB) than those with chronic hepatitis B(CHB) and liver cirrhosis(LC) (both P < 0.05), but similar between patients with CHB and LC (P > 0.05). And the expression of HNF3ß was similar among patients with CHB, LC and SHB (P > 0.05 for all pairwise comparison). This suggests that the expression level of HNF4α was different in patients with different outcome of HBV infection, high expression level of HNF4α may correlate with occurrence of SHB.