Sinomenine ester derivative inhibits glioblastoma by inducing mitochondria-dependent apoptosis and autophagy by PI3K/AKT/mTOR and AMPK/mTOR pathway.
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ABSTRACT:
SUBMITTER: Zheng X
PROVIDER: S-EPMC8642618 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Glioblastoma is a high-grade glioma with poor prognosis even after surgery and standard therapy. Here, we asked whether carnosine (β-alanyl-L-histidine), a naturally occurring dipeptide, exert its anti-neoplastic effect on glioblastoma cells via PI3K/Akt/mTOR signaling. Therefore, glioblastoma cells from the lines U87 and T98G were exposed to carnosine, to the mTOR inhibitor rapamycin and to the PI3K inhibitor Ly-294,002. Pyruvate dehydrogenase kinase (PDK4) expression, known to be a target of PI3K/Akt/mTOR, and which is also affected by carnosine, was analyzed by RT-qPCR, and reporter gene assays with the human PDK4 promoter were performed. Cell viability was assessed by cell-based assays and mTOR and Akt phosphorylation by Western blotting. Rapamycin and Ly-294,002 increased PDK4 mRNA expression in both cell lines but significance was only reached in U87. Carnosine significantly increased expression in both lines. A significant combinatorial effect of carnosine was only detected in U87 when the dipeptide was combined with Ly-294,002. Reporter gene assays revealed no specific effect of carnosine on the human PDK4 promoter, whereas both inhibitors increased reporter gene expression. Rapamycin reduced phosphorylation of mTOR, and Ly-294,002 that of Akt. A significant reduction of Akt phosphorylation was observed in the presence of carnosine in U87 but not in T98G, and carnosine had no effect on mTOR phosphorylation. Cell viability as determined by ATP in cell lysates was reduced only in the presence of carnosine. We conclude that carnosine's anti-neoplastic effect is independent from PI3K/Akt/mTOR signaling. As the dipeptide reduced viability in tumor cells that do not respond to PI3K or mTOR inhibitors, it appears to be worth to further investigate the mechanisms by which carnosine exerts its anti-tumor effect and to consider it for therapy, especially as it is a naturally occurring compound that has already been used for the treatment of other diseases without indication of side-effects.
| S-EPMC6597087 | biostudies-literature
Project description:Glioblastoma multiform (GBM) is the most common malignant glioma of all the brain tumors and currently effective treatment options are still lacking. GBM is frequently accompanied with overexpression and/or mutation of epidermal growth factor receptor (EGFR), which subsequently leads to activation of many downstream signal pathways such as phosphatidylinositol 3-kinase (PI3K)/Akt/rapamycin-sensitive mTOR-complex (mTOR) pathway. Here we explored the reason why inhibition of the pathway may serve as a compelling therapeutic target for the disease, and provided an update data of EFGR and PI3K/Akt/mTOR inhibitors in clinical trials.
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Project description:The progression of cancer through local expansion and metastasis is well recognized, but preventing these characteristic cancer processes is challenging. To this end, a new strategy is required. In this study, we presented a novel dual functional podophyllotoxin derivative, 2-pyridinealdehyde hydrazone dithiocarbamate S-propionate podophyllotoxin ester (PtoxPdp), which inhibited both matrix metalloproteinases and Topoisomerase II. This new podophyllotoxin derivative exhibited significant anti-proliferative, anti-metastatic that correlated with the downregulation of matrix metalloproteinase. In a xenograft animal local expansion model, PtoxPdp was superior to etoposide in tumor repression. A preliminary mechanistic study revealed that PtoxPdp induced apoptosis and autophagy via the PI3K/AKT/mTOR pathway. Furthermore, PtoxPdp could also inhibit epithelial-mesenchymal transition, which was achieved by downregulating both PI3K/AKT/mTOR and NF-κB/Snail pathways. Taken together, our results reveal that PtoxPdp is a promising antitumor drug candidate.
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Project description:Background and purposeRecent reports have suggested that salidroside could protect cardiomyocytes from oxidative injury and stimulate glucose uptake in skeletal muscle cells by activating AMP-activated protein kinase (AMPK). The aim of this study was to evaluate the therapeutic effects of salidroside on diabetic mice and to explore the underlying mechanisms.Experimental approachThe therapeutic effects of salidroside on type 2 diabetes were investigated. Increasing doses of salidroside (25, 50 and 100 mg·kg(-1) ·day(-1)) were administered p.o. to db/db mice for 8 weeks. Biochemical analysis and histopathological examinations were conducted to evaluate the therapeutic effects of salidroside. Primary cultured mouse hepatocytes were used to further explore the underlying mechanisms in vitro.Key resultsSalidroside dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Hypolipidaemic effects and amelioration of liver steatosis were observed after salidroside administration. In vitro, salidroside dose-dependently induced an increase in the phosphorylations of AMPK and PI3K/Akt, as well as glycogen synthase kinase 3β (GSK3β) in hepatocytes. Furthermore, salidroside-stimulated AMPK activation was found to suppress the expression of PEPCK and glucose-6-phosphatase. Salidroside-induced AMPK activation also resulted in phosphorylation of acetyl CoA carboxylase, which can reduce lipid accumulation in peripheral tissues. In isolated mitochondria, salidroside inhibited respiratory chain complex I and disturbed oxidation/phosphorylation coupling and moderately depolarized the mitochondrial membrane potential, resulting in a transient increase in the AMP/ATP ratio.Conclusions and implicationsSalidroside exerts an antidiabetic effect by improving the cellular metabolic flux through the activation of a mitochondria-related AMPK/PI3K/Akt/GSK3β pathway.
| S-EPMC4500366 | biostudies-literature
Project description:Curcumin is a chemical constituent extracted from Curcuma longa L. Several clinical and preclinical studies have demonstrated that it can mitigate exercise fatigue, but the exact mechanism is still unknown. Therefore, we applied a mouse model of exercise fatigue to investigate the possible molecular mechanisms of curcumin's anti-fatigue effect. Depending on body mass, Kunming mice were randomly divided into control, caffeine (positive drug), and curcumin groups, and were given 28 days intragastric administration. Both the caffeine group and curcumin group showed significant improvement in exercise fatigue compared to the control group, as evidenced by the increase in time to exhaustion, as well as the higher quadriceps coefficient, muscle glycogen (MG) content, and increase in the expression of Akt, AMPK, PI3K, and mTOR proteins. While the curcumin group also significantly improved the exercise fatigue of the mice, demonstrating a lower AMP/ATP ratio and lactic acid (LA) content, and increased glycogen synthase (GS), and myonectin content compared to the caffeine group. Therefore, in the present study, we found that curcumin can exert a similar anti-fatigue effect to caffeine and may act by regulating energy metabolism through modulating the expression of the proteins in the PI3K/Akt/AMPK/mTOR pathway.
| S-EPMC10085593 | biostudies-literature
Project description:BackgroundExtracellular adenosine triphosphate (ATP) functions as a novel danger signal that boosts antitumor immunity and can also directly kill tumor cells. We have previously reported that chronic exposure of tumor cells to ATP provokes P2X7-mediated tumor cell death, by as yet incompletely defined molecular mechanisms.Methodology/principal findingsHere, we show that acute exposure of tumor cells to ATP results in rapid cytotoxic effects impacting several aspects of cell growth/survival, leading to inhibition of tumor growth in vitro and in vivo. Using agonist and antagonist studies together with generation of P2X7 deficient tumor cell lines by lentiviral shRNA delivery system, we confirm P2X7 to be the central control node transmitting extracellular ATP signals. We identify that downstream intracellular signaling regulatory networks implicate two signaling pathways: the known P2X7-PI3K/AKT axis and remarkably a novel P2X7-AMPK-PRAS40-mTOR axis. When exposed to high levels of extracellular ATP, these two signaling axes perturb the balance between growth and autophagy, thereby promoting tumor cell death.ConclusionsOur study defines novel molecular mechanisms underpinning the antitumor actions of P2X7 and provides a further rationale for purine-based drugs in targeted cancer therapy.
| S-EPMC3615040 | biostudies-literature
Project description:Glioblastoma multiforme (GBM) is the most frequent and lethal cancer derived from the central nervous system, of which the mesenchymal (MES) subtype seriously influences the survival and prognosis of patients. NAD(P)H: quinone acceptor oxidoreductase 1 (NQO1) serves an important role in the carcinogenesis and progression of various types of cancer; however, the specific mechanism underlying the regulatory effects of NQO1 on GBM is unclear. Thus, the present study aimed to explore the role and mechanism of NQO1 in GBM progression. The results of bioinformatics analysis and immunohistochemistry showed that high expression of NQO1 was significantly related to the MES phenotype of GBM and shorter survival. In addition, MTT, colony formation, immunofluorescence and western blot analyses, and lung metastasis model experiments suggested that silencing NQO1 inhibited the proliferation and metastasis of GBM cells in vitro and in vivo. Furthermore, western blotting showed that the activity of the PI3K/Akt/mTOR signaling pathway was revealed to be inhibited by downregulation of NQO1 expression, whereas it was enhanced by overexpression of NQO1. Notably, co‑immunoprecipitation and ubiquitination experiments suggested that Snail was considered an important downstream target of NQO1 in GBM cells. Snail knockdown could eliminate the promoting effect of ectopic NQO1 on the proliferation and invasion of GBM cells, and reduce its effects on the activity of PI3K/Akt/mTOR signaling pathway. These results indicated that NQO1 could promote GBM aggressiveness by activating the PI3K/Akt/mTOR signaling pathway in a Snail‑dependent manner, and NQO1 and its relevant pathways may be considered novel targets for GBM therapy.
| S-EPMC10552716 | biostudies-literature
Project description:BackgroundN6-methyladenosine (m6A) modification, as the most abundant RNA modification, widely participates in the physiological process and is involved in multiple disease progression, especially cancer. YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) is a pivotal m6A "reader" protein, which has been reported in multiple cancers. However, the role and molecular mechanism of YTHDF1 in HCC are still not fully elucidated.MethodsBased on various bioinformatics databases, q-RT PCR, western blot, and a tissue microarray containing 90 HCC samples, we examined the expression of YTHDF1 in HCC. Then, we applied the loss-of-function experiments to explore the role of YTHDF1 in HCC by in vitro and in vivo assays. Finally, we performed the gene set enrichment analysis (GSEA) to predict the potential signaling pathway of YTHDF1 involved in HCC and further verified this prediction.ResultsYTHDF1 was overexpressed in HCC and associated with HCC grade. Depletion of YTHDF1 markedly impaired the proliferation, migration, invasion, and cell cycle process of HCC cells. Mechanistically, YTHDF1 promoted the growth of HCC cells via activating the PI3K/AKT/mTOR signaling pathway. Moreover, we also demonstrated that the epithelial-mesenchymal transition (EMT) mediated the promoting effect of YTHDF1 on the migration and invasion of HCC cells.ConclusionsYTHDF1 contributes to the progression of HCC by activating PI3K/AKT/mTOR signaling pathway and inducing EMT.
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Project description:The present study examined the expression of mammalian target of rapamycin (mTOR) and mutations in the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway in 54 patients with typical carcinoid tumours (TC) or atypical carcinoid tumours (AC). In total, 54 bronchopulmonary neuroendocrine tumour (NET) surgical specimens, consisting of 17 TC, 8 AC, 17 large-cell neuroendocrine carcinoma (LCNEC), and 12 small-cell lung carcinoma (SCLC) samples, were tested for mTOR by immunohistochemistry, and 104 exon sites were tested in the PI3K/AKT/mTOR pathway by nested polymerase chain reaction. It was found that the positive rates for mTOR expression in TC/AC and LCNEC/SCLC were 60 (15/25) and 55.2% (16/29), respectively. In total, 4 missense mutations were found in 3 patients with TC/AC, including mutations in exon 48 of mTOR (c.6667C>T), exon 21 of tuberous sclerosis complex (TSC) 1 (c.2765G>A), and exons 12 (c.1265C>T) and 19 (c.2148C>T) of TSC2. To the best of our knowledge, mutations in exon 48 of mTOR and exon 21 of TSC1 have not been previously reported. Tissues from patients with single mutations exhibited strong positive mTOR immunohistochemical staining, and tissues from patients with double mutations were weakly positive. The same mutations were not observed in SCLC or LCNEC. In conclusion, gene mutations were observed and an association between the gene mutations and mTOR expression were indicated in the PI3K/AKT/mTOR pathway in TC/AC tumours. Those mutations may be driver genes and treatment targets.
| S-EPMC5529984 | biostudies-other
Project description:Activation of the phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is common in breast cancer. There is preclinical data to support inhibition of the pathway, and phase I to III trials involving inhibitors of the pathway have been or are being conducted in solid tumors and breast cancer. Everolimus, an mTOR inhibitor, is currently approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In this review, we summarise the efficacy and toxicity findings from the randomised clinical trials, with simplified guidelines on the management of potential adverse effects. Education of healthcare professionals and patients is critical for safety and compliance. While there is some clinical evidence of activity of mTOR inhibition in HR-positive and HER2-positive breast cancers, the benefits may be more pronounced in selected subsets rather than in the overall population. Further development of predictive biomarkers will be useful in the selection of patients who will benefit from inhibition of the PI3K/Akt/mTOR (PAM) pathway.
| S-EPMC4706528 | biostudies-literature