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Research Paper
Activation of Polyamine Catabolism by N1, N11-Diethylnorspermine Alters the Cellular Localization of mTOR and Downregulates mTOR Protein Level in Glioblastoma Cells
Rongcai Jiang, Woonyoung Choi, Limei Hu, Eugene W. Gerner, Stanley R. Hamilton and Wei Zhang
volume 6 | issue 10
October 2007Pages: 1644 - 1648
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N1, N11-Diethylnorspermine (DENSPM) is a spermine analog and prototype anti-cancer drug that depletes cellular polyamine, increases cellular oxidative stress through the generation of H2O2, 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, p70S6K, phosphorylated p70S6K, 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 down-regulated, 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.
Authors
Rongcai Jiang
Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; Tianjin General Hospital, Tianjin Medical University, Tianjin, PR China
Woonyoung Choi
Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX
Limei Hu
Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX
Eugene W. Gerner
Department of Cell Biology & Anatomy, Arizona Cancer Center, University of Arizona, Tucson, Arizona
Stanley R. Hamilton
Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX
Wei Zhang
Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.