Inflammation and polyamine catabolism: the good, the bad and the ugly.
The induction of polyamine catabolism by specific anti-tumour polyamine analogues has increased interest in the roles polyamine catabolism play in cell growth, death and response to various anti-tumour agents. The relatively recent finding of an inducible mammalian spermine oxidase (SMO/PAOh1), in addition to the two-step spermidine/spermine N(1)-acetyltransferanse (SSAT)/N(1)-acetylpolyamine oxidase (APAO) catabolic pathway, underscores the complexities of the regulation of polyamine catabolism by various stimuli. Furthermore, recent data indicate that infectious agents and mediators of inflammation can also up-regulate polyamine catabolism. Induction of SSAT by these agents can reduce intracellular polyamine concentrations and cell growth rate, thus providing a beneficial mechanism by which cells may adapt to inflammatory stress. However, increased polyamine catabolism can also result in substantial increases in intracellular reactive oxygen species (ROS) through the production of H(2)O(2) as a by-product of either APAO or SMO/PAOh1 activity. This increased generation of ROS can have different results, depending on the mechanism of induction and cell types involved. Targeted killing of tumour cells by agents that stimulate SSAT/APAO and/or SMO/PAOh1 is obviously a 'good' effect. However, induction of SMO/PAOh1 by inflammation or infectious agents has the potential to produce sufficient ROS in normal, non-tumour cells to lead to DNA damage, mutation and, potentially, carcinogenic transformation ('bad'). The variation in the induction of these polyamine catabolic enzymes, as well as the level and timing of this induction will dictate the cellular outcome in the presence of both desirable and undesirable effects ('ugly'). Here we discuss the relative role of each of the steps in polyamine catabolism in response to inflammatory stress.
Babbar
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The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21231, USA.
Murray-Stewart
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Casero
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D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000503:physiopathology; D011073:Polyamines / Q000378:metabolism*; D015398:Signal Transduction
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D011073:Polyamines