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Carnosine inhibits glioblastoma growth independent from PI3K/Akt/mTOR signaling.

ABSTRACT: Glioblastoma is a high-grade glioma with poor prognosis even after surgery and standard therapy. Here, we asked whether carnosine (?-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.

SUBMITTER: Oppermann H

PROVIDER: S-EPMC6597087 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Carnosine inhibits glioblastoma growth independent from PI3K/Akt/mTOR signaling.

Oppermann Henry H Faust Helene H Yamanishi Ulrike U Meixensberger Jürgen J Gaunitz Frank F

PloS one 20190627 6

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 P ...[more]

PMID: 31247000

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Project description:BackgroundGlobally, esophageal cancer ranks as the seventh most common cancer. Esophageal squamous cell carcinoma (ESCC) is one of its major histological types. ESCC accounts for the vast majority of cases in China, and the mortality rate is high. Cisplatin, the standard adjuvant chemotherapy drug for ESCC, has a modest response rate due to the development of drug resistance. Hinokiflavone (HF) is a natural biflavonoid compound with anti-melanoma activity. However, its anti-tumor effect on ESCC and the underlying mechanisms remain largely unknown.MethodsThe ESCC cell lines KYSE150 and TE14 were used. The cell counting kit-8 assay and flow cytometry analysis, along with colony formation, EdU, wound healing, and Transwell migration assays, were performed to assess cell characteristics (viability, migration, invasion, and apoptosis) following treatment with HF. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), western blotting, and molecular docking were used to investigate the pathways potentially modulated by HF. In vivo anti-tumor effects of HF were also investigated using a mouse xenograft model.ResultsOur findings revealed that HF inhibited ESCC cell proliferation. Hoechst 33342 staining, annexin V-FITC/PI staining, and western blotting confirmed that HF causes caspase-dependent apoptosis. KEGG pathway enrichment analysis and western blotting indicated that the PI3K/AKT/mTOR pathway played an important role in the process of HF-induced apoptosis. Furthermore, HF effectively impaired the migration and invasion abilities of KYSE150 cells and downregulated the expression of the matrix metalloproteinases (MMP) MMP2 and MMP9. HF inhibited tumor growth and exhibited minimal toxicity in the organs of the KYSE150 xenograft model.ConclusionThis is the first study to demonstrate the inhibition of ESCC growth and progression by HF. The underlying mechanism is through blocking the PI3K/AKT/mTOR signaling pathway, thereby inhibiting cell proliferation and inducing apoptosis. HF can be used as a complementary/alternative agent for ESCC therapy.

Dataset Information

Carnosine inhibits glioblastoma growth independent from PI3K/Akt/mTOR signaling.

Publications

Carnosine inhibits glioblastoma growth independent from PI3K/Akt/mTOR signaling.

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