Subcellular distribution of spermidine/spermine <i>N</i><sup>1</sup>‐acetyltransferase

Holst, C. Martina; Nevsten, Pernilla; Johansson, Fredrik; Carlemalm, Eric; Oredsson, Stina

doi:10.1016/j.cellbi.2007.08.008

Cited by 18 publications

(15 citation statements)

References 37 publications

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“…The uptake of JC-1 is dependent on the mitochondrial transmembrane potential [39]. We have seen the same phenomenon using another mitochondrial stain [50]. Our data point to a polyamine analogue-induced increase in mitochondrial respiration, thus supporting the notion that DC m is increased in DENSPM-treated cells [11,26].…”

Section: Discussionsupporting

confidence: 84%

Molecular mechanisms underlying N 1, N 11-diethylnorspermine-induced apoptosis in a human breast cancer cell line

et al. 2008

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Polyamine analogue treatment results in growth inhibition and sometimes in cell death. Therefore, polyamine analogues are considered in the treatment of cancer; however, the cellular properties that govern sensitivity are not known. The objective of this study was to elucidate molecular mechanisms behind apoptosis induced by the polyamine analogue N, N-diethylnorspermine (DENSPM). Four different breast cancer cell lines were treated with DENSPM. Cell death was evaluated with flow cytometry and a caspase 3 assay. The levels of a number of proapoptotic and antiapoptotic proteins in subcellular compartments were evaluated with western blot. In the most sensitive cell line, DENSPM treatment induced the release of cytochrome c from mitochondria, resulting in activation of caspase 3 but without decreasing the mitochondrial transmembrane potential. However, in the three other cell lines DENSPM treatment did not induce extensive cell death. This is partly explained by the high levels of antiapoptotic proteins Bcl-2 and Bad and low levels of proapoptotic proteins Bax and procaspase 3 in these three cell lines. The results are also partly explained by the degree of activation of the catabolic enzyme spermidine/spermine-N-acetyltransferase and polyamine pool reduction achieved by DENSPM treatment. Our results show that the protein profile of proapoptotic and antiapoptotic proteins may contribute to the outcome to treatment with the polyamine analogue DENSPM. The results also indicate that it should be possible to find molecular markers for sensitivity to DENSPM that could be used in the clinic to predict sensitivity to a polyamine analogue.

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Section: Discussionsupporting

confidence: 84%

Molecular mechanisms underlying N 1, N 11-diethylnorspermine-induced apoptosis in a human breast cancer cell line

et al. 2008

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“…SSAT is generally considered to be predominantly cytosolic, but a recent study indicated a mitochondrial location for a large portion of the SSAT after induction by BE-3-3-3 in a breast cancer cell line (62). It has also been reported that SSAT is phosphorylated by casein kinase-1 and -2 and that this affects binding to mitochondrial membranes (17).…”

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confidence: 97%

Spermidine/spermine-N¹-acetyltransferase: a key metabolic regulator

Pegg¹

2008

American Journal of Physiology-Endocrinology and Metabolism

304

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Spermidine/spermine-N(1)-acetyltransferase (SSAT) regulates cellular polyamine content. Its acetylated products are either excreted from the cell or oxidized by acetylpolyamine oxidase. Since polyamines play critical roles in normal and neoplastic growth and in ion channel regulation, SSAT is a key enzyme in these processes. SSAT is very highly regulated. Its content is adjusted in response to alterations in polyamine content to maintain polyamine homeostasis. Certain polyamine analogs can mimic the induction of SSAT and cause a loss of normal polyamines. This may have utility in cancer chemotherapy. SSAT activity is also induced via a variety of other stimuli, including toxins, hormones, cytokines, nonsteroidal anti-inflammatory agents, natural products, and stress pathways, and by ischemia-reperfusion injury. These increases are initiated by alterations in Sat1 gene transcription reinforced by alterations at the other regulatory steps, including protein turnover, mRNA processing, and translation. Transgenic manipulation of SSAT activity has revealed that SSAT activity links polyamine metabolism to lipid and carbohydrate metabolism by means of alterations in the content of acetyl-CoA and ATP. A high level of SSAT stimulates flux through the polyamine biosynthetic pathway, since biosynthetic enzymes are induced in response to the fall in polyamines. This sets up a futile cycle in which ATP is used to generate S-adenosylmethionine for polyamine biosynthesis and acetyl-CoA is consumed in the acetylation reaction. A variety of other effects of increased SSAT activity include death of pancreatic cells, blockage of regenerative tissue growth, behavioral changes, keratosis follicularis spinulosa decalvans, and hair loss. These are very likely due to changes in polyamine and putrescine levels, although increased oxidative stress via the oxidation of acetylated polyamines may also contribute. Recently, it was found that the SSAT protein and/or a related protein, thialysine acetyltransferase, interacts with a number of other important proteins, including the hypoxia-inducible factor-1 alpha-subunit, the p65 subunit of NF-kappaB, and alpha9beta1-integrin, altering the function of these proteins. It is not yet clear whether this functional alteration involves protein acetylation, local polyamine concentration changes, or other effects. It has been suggested that SSAT may also be a useful target in diseases other than cancer, but the wide-ranging physiological and pathophysiological effects of altered SSAT expression will require very careful limitation of such strategies to the relevant cells to avoid toxic effects.

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“…Under DENSpm-induced conditions, using immunohistochemistry and immunocytochemistry, SSAT has been detected in the cytoplasm of human adenocarcinoma A549 cells and in the cytoplasm, nucleus and mitochondria of human breast cancer L56Br-C1 cells respectively [23,24]. We were not able to detect the SSAT–EGFP under the fluorescent microscope unless DENSpm or CPENSpm was added to the growth medium.…”

Section: Discussionmentioning

confidence: 95%

Spermine analogue-regulated expression of spermidine/spermine N1-acetyltransferase and its effects on depletion of intracellular polyamine pools in mouse fetal fibroblasts

Uimari

Keinänen

Karppinen

et al. 2009

Biochemical Journal

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SSAT (Spermidine/spermine N1-acetyltransferase, also known as SAT1), the key enzyme in the catabolism of polyamines, is turned over rapidly and there is only a low amount present in the cell. In the present study, the regulation of SSAT by spermine analogues, the inducers of the enzyme, was studied in wild-type mouse fetal fibroblasts, expressing endogenous SSAT, and in the SSAT-deficient mouse fetal fibroblasts transiently expressing an SSAT–EGFP (enhanced green fluorescent protein) fusion gene. In both cell lines treatments with DENSpm (N1,N11-diethylnorspermine), CPENSpm (N1-ethyl-N11-[(cyclopropyl)-methy]-4,8-diazaundecane) and CHENSpm (N1-ethyl-N11-[(cycloheptyl)methy]-4,8-diazaundecane) led to high, moderate or low induction of SSAT activity respectively. The level of activity detected correlated with the presence of SSAT and SSAT– EGFP proteins, the latter localizing both in the cytoplasm and nucleus. RT–PCR (reverse transcription–PCR) results suggested that the analogue-affected regulation of SSAT–EGFP expression occurred, mainly, after transcription. In wild-type cells, DENSpm increased the amount of SSAT mRNA, and both DENSpm and CHENSpm affected splicing of the SSAT pre-mRNA. Depleted intracellular spermidine and spermine levels inversely correlated with detected SSAT activity. Interestingly, the analogues also reduced polyamine levels in the SSAT-deficient cells expressing the EGFP control. The results from the present study show that the distinct SSAT regulation by different analogues involves regulatory actions at multiple levels, and that the spermine analogues, in addition to inducing SSAT, lower intracellular polyamine pools by SSAT-independent mechanisms.

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Subcellular distribution of spermidine/spermine N¹‐acetyltransferase

Cited by 18 publications

References 37 publications

Molecular mechanisms underlying N 1, N 11-diethylnorspermine-induced apoptosis in a human breast cancer cell line

Molecular mechanisms underlying N 1, N 11-diethylnorspermine-induced apoptosis in a human breast cancer cell line

Spermidine/spermine-N¹-acetyltransferase: a key metabolic regulator

Spermine analogue-regulated expression of spermidine/spermine N1-acetyltransferase and its effects on depletion of intracellular polyamine pools in mouse fetal fibroblasts

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Subcellular distribution of spermidine/spermine N1‐acetyltransferase

Cited by 18 publications

References 37 publications

Molecular mechanisms underlying N 1, N 11-diethylnorspermine-induced apoptosis in a human breast cancer cell line

Molecular mechanisms underlying N 1, N 11-diethylnorspermine-induced apoptosis in a human breast cancer cell line

Spermidine/spermine-N1-acetyltransferase: a key metabolic regulator

Spermine analogue-regulated expression of spermidine/spermine N1-acetyltransferase and its effects on depletion of intracellular polyamine pools in mouse fetal fibroblasts

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Subcellular distribution of spermidine/spermine N¹‐acetyltransferase

Spermidine/spermine-N¹-acetyltransferase: a key metabolic regulator