TY - JOUR
T1 - Activation of polyamine catabolism by N1, N11-diethylnorspermine alters the cellular localization of mTOR and downregulates mTOR protein level in glioblastoma cells
AU - Jiang, Rongcai
AU - Choi, Woonyoung
AU - Hu, Limei
AU - Gerner, Eugene W.
AU - Hamilton, Stanley R.
AU - Zhang, Wei
N1 - Funding Information:
mammalian target of The mechanism of such polyamine analog-induced cell death is still not well under-rapamycin stood, information that is important to the development of potentially more potent PBS phosphate buffered polyamine analogs. We do know, however, that DENSPM induces spermidine/spermine TMZ temazolomide acetyltransferase (SSAT) expression, which converts spermine and spermidine to their acetylated forms. Spermine, acetylated spermine, and acetylated spermidine can then serve ACKnoWLEdGEmEntS as substrates for spermine oxidase or polyamine oxidase in the production of H2O2,13-15 We thank Ms. Beth Notzon for editorial which is believed to be at least one of the initiating factors in DENSPM-induced cell assistance. ©2008 LANDES BIOSCIENCEThis work was partially supported death. Other effects of DENSPM-induced cell death include damage to mitochondria by funding from the National Foundation for and the release of cytochrome C from mitochondria, but the activation of caspase 3 and 8 Cancer Research and Anthony Bullock III has not been commonly observed, which rules out the pathway as the primary apoptotic Research Fund. mechanism.7 We have similarly observed that neither the caspase cascade is activated nor the cyto-chrome C redistributed in glioblastoma cell lines treated with DENSPM,11 which indicates that DENSPM induces apoptosis in glioblastoma cells through an alternative pathway. In
PY - 2007/10
Y1 - 2007/10
N2 - 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 H 2O2 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 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.
AB - 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 H 2O2 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 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.
KW - DENSPM
KW - Glioblastoma
KW - Polyamine
KW - mTOR
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U2 - 10.4161/cbt.6.10.4800
DO - 10.4161/cbt.6.10.4800
M3 - Article
C2 - 17921698
AN - SCOPUS:41649120239
SN - 1538-4047
VL - 6
SP - 1644
EP - 1648
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 10
ER -