Smurf1 Suppression Enhances Temozolomide Chemosensitivity in Glioblastoma by Facilitating PTEN Nuclear Translocation.

The tumor suppressor PTEN mainly inhibits the PI3K/Akt pathway in the cytoplasm and maintains DNA stability in the nucleus. The status of PTEN remains therapeutic effectiveness for chemoresistance of the DNA alkylating agent temozolomide (TMZ) in glioblastoma (GB). However, the underlying mechanisms of PTEN's interconnected role in the cytoplasm and nucleus in TMZ resistance are still unclear. In this study, we report that TMZ-induced PTEN nuclear import depends on PTEN ubiquitylation modification by Smurf1. The Smurf1 suppression decreases the TMZ-induced PTEN nuclear translocation and enhances the DNA damage. In addition, Smurf1 degrades cytoplasmic PTEN K289E (the nuclear-import-deficient PTEN mutant) to activate the PI3K/Akt pathway under TMZ treatment. Altogether, Smurf1 interconnectedly promotes PTEN nuclear function (DNA repair) and cytoplasmic function (activation of PI3K/Akt pathway) to resist TMZ. These results provide a proof-of-concept demonstration for a potential strategy to overcome the TMZ resistance in PTEN wild-type GB patients by targeting Smurf1.

Effects of dapagliflozin in the progression of atherosclerosis in patients with type 2 diabetes: a meta-analysis of randomized controlled trials.

AIMS: At present, an increasing number of studies are trying to determine whether dapagliflozin has a significant effect on the occurrence and development of atherosclerosis in patients with type 2 diabetes mellitus (T2DM), but there is no consensus. In addition, the former meta-analyses, relying on only a few previous studies and a minimal number of research indicators, have not been able to draw sufficient conclusions simultaneously. Consequently, we conducted a meta-analysis to evaluate the effectiveness of dapagliflozin in the occurrence and development of atherosclerosis in patients with T2DM. METHODS: We searched electronic databases (PubMed, Embase, Cochrane, and Scopus) and reference lists in relevant papers for articles published in 2011-2021. We selected studies that evaluated the effects of dapagliflozin on the risk factors related to the occurrence or development of atherosclerosis in patients with T2DM. A fixed or random-effect model calculated the weighted average difference of dapagliflozin on efficacy, and the factors affecting heterogeneity were determined by Meta-regression analysis. RESULTS: Twelve randomized controlled trials (18,758 patients) were incorporated in our meta-analysis. In contrast with placebo, dapagliflozin was associated with a significantly increase in high density lipoprotein-cholesterol (HDL-C) [MD = 1.39; 95% CI (0.77, 2.01); P < 0.0001], Δflow-mediated vasodilatation (ΔFMD) [MD = 1.22; 95% CI (0.38, 2.06); P = 0.005] and estimated Glomerular Filtration Rate(eGFR) [MD = 1.94; 95% CI (1.38, 2.51); P < 0.00001]. Furthermore, dapagliflozin had a tremendous advantage in controlling triglycerides (TG) in subgroups whose baseline eGFR < 83 ml/min/1.73m2 [MD = - 10.38; 95% CI (- 13.15, - 7.60); P < 0.00001], systolic blood pressure (SBP) [MD = - 2.82; 95% CI (- 3.22, - 2.42); P < 0.00001], HbA1c, BMI, body weight and waist circumference. However, dapagliflozin has an adverse effect on increasing total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C). Besides, there were no significant changes in other indicators, including adiponectin and C-peptide immunoreactivity. CONCLUSIONS: Our pooled analysis suggested that dapagliflozin has a terrifically better influence over HDL-C, ΔFMD, and eGFR, and it concurrently had a tremendous advantage in controlling TG, SBP, DBP, HbA1c, BMI, body weight, and waist circumference, but it also harms increasing TC and LDL-C. Furthermore, this study found that the effect of dapagliflozin that decreases plasma levels of TG is only apparent in subgroups of baseline eGFR < 83 ml/min/1.73m2, while the subgroup of baseline eGFR ≥ 83 ml/min/1.73m2 does not. Finally, the above results summarize that dapagliflozin could be a therapeutic option for the progression of atherosclerosis in patients with T2DM. Systematic review registration PROSPERO CRD42021278939.

Overexpressed Smurf1 is degraded in glioblastoma cells through autophagy in a p62-dependent manner.

Homologous to E6AP C-terminus (HECT)-type E3 ubiquitin ligase SMAD-specific E3 ubiquitin protein ligase 1 (Smurf1) was originally identified to ubiquitinate Smad protein in the TGF-ß/BMP signaling pathway. Recently, Smurf1 has been reported to promote tumorigenesis by regulating multiple biological processes. High expression of Smurf1 plays a vital role in brain tumor progression by mediating aberrant cell signaling pathways. Previous reports have shown that Smurf1 is degraded mainly through the ubiquitin-proteasome system, but it remains unclear whether Smurf1 is degraded by autophagy in tumor cells. In this study, we show that autophagy activators promote Smurf1 degradation in glioblastoma (GB) cells. The autophagy receptor p62 colocalizes with ubiquitinated substrates to promote sequestration of cytoplasm cargo into the autophagosome. We report that autophagic degradation of Smurf1 is dependent on p62. Moreover, the autophagic degradation of Smurf1 is prevented in the absence of the HECT domain or E3 ubiquitin ligase activity. We further proved that activation of autophagy leads to a decrease of Smurf1 and the inhibition of the phosphoinositide 3-kinase/protein kinase B signaling pathway in GB cells. Our results suggest that enhancement of autophagic degradation of Smurf1 may be a potential approach to treating GB.

Smurf1 silencing restores PTEN expression that ameliorates progression of human glioblastoma and sensitizes tumor cells to mTORC1/C2 inhibitor Torin1.

Amplification of ubiquitin E3 ligase Smurf1 promotes degradation of PTEN leading to hyperactivation of the Akt/mTORC1 pathway. However, inhibitors of this pathway have not hitherto yielded promising results in clinical studies because of strong drug resistance. Here, we investigated Smurf1 expression in various glioblastoma (GB) cell lines and patient tissues. The therapeutic efficacy of Smurf1 silencing and Torin1 treatment was assessed in GB cells and orthotopic mouse model. We found Smurf1 loss elevates PTEN levels that interrupt the epidermal growth factor receptor pathway activity. Cotreatment with Smurf1 silencing and mTORC1/C2 inhibitor Torin1 remarkably decreased phosphorylation of Akt, and mTORC1 downstream targets 4EBP1 and S6K resulting in synergistic inhibitory effects. Smurf1 knockdown in orthotopic GB mouse model impaired tumor growth and enhanced cytotoxicity of Torin1. Together, these findings suggest a rational combination of Smurf1 inhibition and Torin1 as a promising new avenue to circumvent PI3K/Akt pathway-driven tumor progression and drug resistance.

Identification of the Prognostic Signatures of Glioma With Different PTEN Status.

The high-grade glioma is characterized by cell heterogeneity, gene mutations, and poor prognosis. The deletions and mutations of the tumor suppressor gene PTEN (5%-40%) in glioma patients are associated with worse survival and therapeutic resistance. Characterization of unique prognosis molecular signatures by PTEN status in glioma is still unclear. This study established a novel risk model, screened optimal prognostic signatures, and calculated the risk score for the individual glioma patients with different PTEN status. Screening results revealed fourteen independent prognostic gene signatures in PTEN-wt and three in the -50PTEN-mut subgroup. Moreover, we verified risk score as an independent prognostic factor significantly correlated with tumor malignancy. Due to the higher malignancy of the PTEN-mut gliomas, we explored the independent prognostic signatures (CLCF1, AEBP1, and OS9) for a potential therapeutic target in PTEN-mut glioma. We further separated IDH wild-type glioma patients into GBM and LGG to verify the therapeutic target along with PTEN status, notably, the above screened therapeutic targets are also significant prognostic genes in both IDH-wt/PTEN-mut GBM and LGG patients. We further identified the small molecule compound (+)-JQ1 binds to all three targets, indicating a potential therapy for PTEN-mut glioma. In sum, gene signatures and risk scores in the novel risk model facilitate glioma diagnosis, prognosis prediction, and treatment.

Correction to: LTBP1 plays a potential bridge between depressive disorder and glioblastoma.

An amendment to this paper has been published and can be accessed via the original article.

LTBP1 plays a potential bridge between depressive disorder and glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM) is the most malignant tumor in human brain. Diagnosis and treatment of GBM may lead to psychological disorders such as depressive and anxiety disorders. There was no research focusing on the correlation between depressive/anxiety disorder and the outcome of GBM. Thus, the aim of this study was to investigate the possibility of depressive/anxiety disorder correlated with the outcome of GBM patients, as well as the overlapped mechanism bridge which could link depressive/anxiety disorders and GBM. METHODS: Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder (GAD-7) were used to investigate the psychological condition of GBM patients in our department. To further explore the potential mechanism, bioinformatic methods were used to screen out genes that could be indicators of outcome in GBM, followed by gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and protein-protein interaction (PPI) analysis. Further, cellular experiments were conducted to evaluate the proliferation, migration capacity of primary GBM cells from the patients. RESULTS: It was revealed that patients with higher PHQ-9 and GAD-7 scores had significantly worse prognosis than their lower-scored counterparts. Bioinformatic mining revealed that LTBP1 could be a potential genetic mechanism in both depressive/anxiety disorder and GBM. Primary GBM cells with different expression level of LTBP1 should significantly different proliferation and migration capacity. GO, KEGG analysis confirmed that extracellular matrix (ECM) was the most enriched function of LTBP1. PPI network showed the interaction of proteins altered by LTBP1. Hub genes COL1A2, COL5A1 and COL10A1, as well as mesenchymal marker CD44 and Vimentin were statistically higher expressed in LTBP1 high group; while proneural marker E-cadherin was significantly higher expressed in low LTBP1 group. CONCLUSION: There is closely correlation between depressive/anxiety disorders and GBM. LTBP1 could be a potential bridge linking the two diseases through the regulation of ECM.