Overexpression of SSAT by DENSPM treatment induces cell detachment and apoptosis in glioblastoma
نویسندگان
چکیده
N1,N11-diethylnorspermine (DENSPM), a polyamine analog that induces expression of spermidine/spermine N1-acetyltransferase (SSAT) and reduces polyamine levels in eukaryotic cells, has demonstrated anticancer effects in many cancer cell types. Gene expression of SSAT after treatment with DENSPM was measured in both U87 and LN229 cells using real-time PCR. Induction of SSAT mRNA using DENSPM resulted in significantly higher levels in U87 cells than in LN229 cells. Furthermore, DENSPM caused marked cell detachment in U87 cells and to a lesser extent in LN229 cells. We hypothesized that elevated SSAT expression plays a key role in DENSPM-induced cell detachment in glioblastoma cells. To investigate whether forced expression of SSAT would lead to reduced cell adhesion and increased cell detachment, we transfected a PCMV-SSAT plasmid into LN229 cells and observed significant cell detachment. In addition, we treated U87 cells with SSAT siRNA together with DENSPM to blunt the induction of SSAT by DENSPM. This resulted in an inhibition of cell detachment in U87 cells compared with the DENSPM treatment alone. Increased SSAT expression by transfection enhanced the DENSPM cell-kill effect in LN229 cells whereas reduction of SSAT by siRNA attenuated the DENSPM cell-kill effect. The protein levels of AKT, mTOR and integrin α5β1, which are members of the cell adhesion and anti-apoptotic signal transduction pathways, were decreased in the PCMV-SSAT transfected LN229 cells. Collectively, these results demonstrate that SSAT induction at least partially plays a role in cell detachment and apoptosis of glioblastoma cells by DENSPM treatment.
منابع مشابه
Activation of polyamine catabolism by N1,N11-diethylnorspermine leads to cell death in glioblastoma.
Glioblastoma multiforme (GBM) is one of the most therapeutically refractory human cancers. Elevated cellular polyamine levels are a common feature of cancer cells, including GBM cells, and the polyamine pathway has been explored as a potential therapeutic target to inhibit polyamine biosynthesis or activate polyamine catabolism. In this study, we investigated the effect of N1,N11-diethyl-norspe...
متن کاملDendrosomal nanocurcumin and p53 overexpression synergistically trigger apoptosis in glioblastoma cells
Objective(s): Glioblastoma is the most lethal tumor of the central nervous system. Here, we aimed to evaluate the effects of exogenous delivery of p53 and a nanoformulation of curcumin called dendrosomal curcumin (DNC), alone and in combination, on glioblastoma tumor cells. Materials and Methods: MTT assay was exploited to measure the viability of U87-MG cells against DNC treatment. Cells were ...
متن کاملSmall interfering RNA suppression of polyamine analog-induced spermidine/spermine n1-acetyltransferase.
N1,N11-diethylnorspermine (DENSPM) is a polyamine analog that down-regulates polyamine biosynthesis and potently upregulates the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT). In certain cells, such as SKMEL-28 human melanoma cells, induction of SSAT is associated with rapid apoptosis. In this study, we used small interfering RNA (siRNA) to examine the role of SSAT ...
متن کاملPolyamine catabolism in platinum drug action: Interactions between oxaliplatin and the polyamine analogue N1,N11-diethylnorspermine at the level of spermidine/spermine N1-acetyltransferase.
A great deal of experimental evidence connects induction of polyamine catabolism via spermidine/spermine N1-acetyltransferase (SSAT) to antiproliferative activity and apoptosis. Following our initial observation from gene expression profiling that platinum drugs induce SSAT, we undertook this present study to characterize platinum drug induction of SSAT and other polyamine catabolic enzymes and...
متن کاملThe role of spermidine/spermine N-acetyltransferase in determining response to chemotherapeutic agents in colorectal cancer cells
Polyamines have been shown to play a role in the growth and survival of several solid tumors, including colorectal cancer. We identified the polyamine catabolic enzyme spermidine/spermine N-acetyltransferase (SSAT) as being one of the most highly inducible genes in two DNA microarray screens to identify novel determinants of response to chemotherapeutic agents in colorectal cancer. SSAT was sho...
متن کامل