Polyamines in Mammalian Biology and Medicine

Williams-Ashman, H.G.; Canellakis, Zoe N.

doi:10.1353/pbm.1979.0013

Cited by 288 publications

(96 citation statements)

References 48 publications

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“…Evidence to support the concept of macrophage activation for either defense or nondefense purposes includes observations from this laboratory (37) that during wound healing, macrophages produce little NO/citrulline, but instead metabolize arginine primarily to ornithine/urea via arginase. This pattern of arginine metabolism makes sense for constructive processes such as wound healing because excess NO would inhibit cell replication/healing, while ornithine could promote cell replication/healing because it is a precursor for polyamines and collagen (7,28,29). That ornithine plays a role in healing is supported by findings that inhibition of ornithine decarboxylase, the ratelimiting enzyme in polyamine synthesis, inhibits healing, while provision of polyamines promotes healing (38,39).…”

Section: Differential Arginine Metabolism By Th1 and Th2 Macrophagesmentioning

confidence: 96%

“…More importantly, however, we also discovered that in response to certain stimuli (LPS), Th2 macrophages not only do not produce NO, but instead increase arginine metabolism to ornithine; Th1 macrophages do not. Because NO inhibits cell replication (7,28,29), while ornithine (as a precursor of polyamines) can stimulate replication, these results suggested that macrophages from Th1 and Th2 mice can influence immune reactions in opposite ways. The results to follow provide evidence to support this postulate and will show that macrophages from Th1 and Th2 strains differentially influence whether Th1, Th2, or other immune response occurs.…”

mentioning

confidence: 99%

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M-1/M-2 Macrophages and the Th1/Th2 Paradigm

Mills

Kincaid

Alt

et al. 2000

The Journal of Immunology

2,695

2,164

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Evidence is provided that macrophages can make M-1 or M-2 responses. The concept of M-1/M-2 fomented from observations that macrophages from prototypical Th1 strains (C57BL/6, B10D2) are more easily activated to produce NO with either IFN-γ or LPS than macrophages from Th2 strains (BALB/c, DBA/2). In marked contrast, LPS stimulates Th2, but not Th1, macrophages to increase arginine metabolism to ornithine. Thus, M-1/M-2 does not simply describe activated or unactivated macrophages, but cells expressing distinct metabolic programs. Because NO inhibits cell division, while ornithine can stimulate cell division (via polyamines), these results also indicate that M-1 and M-2 responses can influence inflammatory reactions in opposite ways. Macrophage TGF-β1, which inhibits inducible NO synthase and stimulates arginase, appears to play an important role in regulating the balance between M-1 and M-2. M-1/M-2 phenotypes are independent of T or B lymphocytes because C57BL/6 and BALB/c NUDE or SCID macrophages also exhibit M-1/M-2. Indeed, M-1/M-2 proclivities are magnified in NUDE and SCID mice. Finally, C57BL/6 SCID macrophages cause CB6F1 lymphocytes to increase IFN-γ production, while BALB/c SCID macrophages increase TGF-β production. Together, the results indicate that M-1- or M-2-dominant macrophage responses can influence whether Th1/Th2 or other types of inflammatory responses occur.

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Section: Differential Arginine Metabolism By Th1 and Th2 Macrophagesmentioning

confidence: 96%

mentioning

confidence: 99%

M-1/M-2 Macrophages and the Th1/Th2 Paradigm

Mills

Kincaid

Alt

et al. 2000

The Journal of Immunology

2,695

2,164

View full text Add to dashboard Cite

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“…The intracellular level of polyamines plays a central role in the control of proliferation (Williams-Ashman & Canellakis, 1979;Pegg, 1988). Tumour promoters such as 12-0-tetradecanoylphorbol-13-acetate have been found to increase the activity of ODC, which catalyses the formation of the polyamine precursor putrescine from ornithine (McCann et al 1992), and so increases the concentration of polyamines in affected tissues (Slaga, 1983).…”

Section: Polyamine Metabolismmentioning

confidence: 99%

Anticarcinogenic Factors in Plant Foods: A New Class of Nutrients?

1994

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“…In addition to synthesizing these molecules for epithelial cell replacement, the gland produces massive quantities of spermine (Spm) for export into reproductive fluids (7)(8)(9)(10). The only major tissue that synthesizes polyamines for export, the prostate, and presumably tumors derived from it, may be dependent on novel and therapeutically exploitable homeostatic mechanisms.…”

mentioning

confidence: 99%

Metabolic and Antiproliferative Consequences of Activated Polyamine Catabolism in LNCaP Prostate Carcinoma Cells

Kee

Vujcic

Merali

et al. 2004

Journal of Biological Chemistry

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Depletion of intracellular polyamine pools invariably inhibits cell growth. Although this is usually accomplished by inhibiting polyamine biosynthesis, we reasoned that this might be more effectively achieved by activation of polyamine catabolism at the level of spermidine/spermine N 1 -acetyltransferase (SSAT); a strategy first validated in MCF-7 breast carcinoma cells. We now examine the possibility that, due to unique aspects of polyamine homeostasis in the prostate gland, tumor cells derived from it may be particularly sensitive to activated polyamine catabolism. Thus, SSAT was conditionally overexpressed in LNCaP prostate carcinoma cells via a tetracycline-regulatable (Tet-off) system. Tetracycline removal resulted in a rapid ϳ10-fold increase in SSAT mRNA and an increase of ϳ20-fold in enzyme activity. SSAT products N 1 -acetylspermidine, N 1 -acetylspermine, and N 1 ,N 12 -diacetylspermine accumulated intracellularly and extracellularly. SSAT induction also led to a growth inhibition that was not accompanied by polyamine pool depletion as it was in MCF-7 cells. Rather, intracellular spermidine and spermine pools were maintained at or above control levels by a robust compensatory increase in ornithine decarboxylase and S-adenosylmethionine decarboxylase activities. This, in turn, gave rise to a high rate of metabolic flux through both the biosynthetic and catabolic arms of polyamine metabolism. Treatment with the biosynthesis inhibitor ␣-difluoromethylornithine during tetracycline removal interrupted flux and prevented growth inhibition. Thus, flux-induced growth inhibition appears to derive from overaccumulation of metabolic products and/or from depletion of metabolic precursors. Metabolic effects that were not excluded as possible contributing factors include high levels of putrescine and acetylated polyamines, a 50% reduction in S-adenosylmethionine, and a 45% decline in the SSAT cofactor acetyl-CoA. Overall, the study demonstrates that activation of polyamine catabolism in LNCaP cells elicits a compensatory increase in polyamine biosynthesis and downstream metabolic events that culminate in growth inhibition.

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Polyamines in Mammalian Biology and Medicine

Cited by 288 publications

References 48 publications

M-1/M-2 Macrophages and the Th1/Th2 Paradigm

M-1/M-2 Macrophages and the Th1/Th2 Paradigm

Anticarcinogenic Factors in Plant Foods: A New Class of Nutrients?

Metabolic and Antiproliferative Consequences of Activated Polyamine Catabolism in LNCaP Prostate Carcinoma Cells

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