Activation of polyamine catabolism by N1, N11-diethylnorspermine alters the cellular localization of mTOR and downregulates mTOR protein level in glioblastoma cells
| Autor: | Wei Zhang, Rongcai Jiang, Eugene W. Gerner, Stanley R. Hamilton, Limei Hu, Woonyoung Choi |
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| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Down-Regulation Antineoplastic Agents P70-S6 Kinase 1 Biology mTORC2 Cell Line Tumor Neoplasms Polyamines Humans Anoikis Diethylnorspermine Protein kinase B PI3K/AKT/mTOR pathway Cellular localization Pharmacology TOR Serine-Threonine Kinases RPTOR Hydrogen Peroxide Cell biology Oncology Molecular Medicine Spermine Glioblastoma Cell Adhesion Molecules Protein Kinases |
| Zdroj: | Cancer Biology & Therapy. 6:1644-1648 |
| ISSN: | 1555-8576 1538-4047 |
| DOI: | 10.4161/cbt.6.10.4800 |
| Popis: | N(1), N(11)-Diethylnorspermine (DENSPM) is a spermine analog and prototype anti-cancer drug that depletes cellular polyamine, increases cellular oxidative stress through the generation of H(2)O(2) and induces the death of multiple types of cancer cells. However, the survival pathways perturbed by DENSPM are uncertain. To identify these pathways, we examined a series of proteins in the phosphoinositide 3-kinase /AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathways in glioblastoma cell lines before and after treatment with DENSPM. We found that DENSPM did not change the protein levels of PI3K but did reduce the levels of AKT, phosphorylated AKT, mTOR, phosphorylated mTOR, p70(S6K), phosphorylated p70(S6K), 4E-BP1, phosphorylated 4E-BP1 and eIF-4B proteins. From this it appears that DENSPM directly targets the mTOR protein level in these glioblastoma cells by inhibiting mTOR-mediated protein synthesis. Immunofluorescence analysis of mTOR showed that DENSPM sequestered mTOR in the perinuclear region of the cells. We also detected a marked collapse of microtubules in U87 cells and a detachment of cells in a process resembling anoikis. We further showed that the levels of many proteins regulating cell growth and cell adhesion were downregulated, suggesting a broad effect of DENSPM on mTOR-mediated protein synthesis. We conclude that the activation of polyamine catabolism alters the cellular location of mTOR, thus negatively affecting mTOR-mediated protein synthesis and leading to the death of glioblastoma cells. |
| Databáze: | OpenAIRE |
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