Polyamine catabolism in carcinogenesis: potential targets for chemotherapy and chemoprevention

Abstract

Polyamines, including spermine, spermidine, and the precursor diamine, putrescine, are naturally occurring polycationic alkylamines that are required for eukaryotic cell growth, differentiation, and survival. This absolute requirement for polyamines and the need to maintain intracellular levels within specific ranges require a highly regulated metabolic pathway primed for rapid changes in response to cellular growth signals, environmental changes, and stress. Although the polyamine metabolic pathway is strictly regulated in normal cells, dysregulation of polyamine metabolism is a frequent event in cancer. Recent studies suggest that the polyamine catabolic pathway may be involved in the etiology of some epithelial cancers. The catabolism of spermine to spermidine utilizes either the one-step enzymatic reaction of spermine oxidase (SMO) or the two-step process of spermidine/spermine N (1)-acetyltransferase (SSAT) coupled with the peroxisomal enzyme N (1)-acetylpolyamine oxidase. Both catabolic pathways produce hydrogen peroxide and a reactive aldehyde that are capable of damaging DNA and other critical cellular components. The catabolic pathway also depletes the intracellular concentrations of spermidine and spermine, which are free radical scavengers. Consequently, the polyamine catabolic pathway in general and specifically SMO and SSAT provide exciting new targets for chemoprevention and/or chemotherapy.

Fig. 1. Polyamine metabolism

Ornithine decarboxylase (ODC) is required for the first step in polyamine synthesis in which ornithine is decarboxylated to produce putrescine. The decarboxylation of S-adenosylmethionine (AdoMet) by AdoMet decarboxylase (AdoMetDC) yields decarboxylated AdoMet, which is then used as the aminopropyl donor for spermidine synthase and spermine synthase to produce the higher polyamines spermidine and spermine, respectively. The conversion to lower level polyamines is made in either two-steps by the spermidine/spermine N¹-acetyltransferase (SSAT)/N¹-acetylpolyamine oxidase (APAO) mechanism or directly from spermine to spermidine by spermine oxidase (SMO). The activities of both APAO and SMO lead to the production of H₂O₂ and the aldehydes 3-acetoaminopropanal (3-AAP) and 3- aminopropanal (3-AP), respectively.

Fig. 2. Potential contributions of polyamine catabolism to cell damage

Polyamine catabolism can be stimulated by various stressors, and transcription of the catabolic enzymes is targeted by transcription factors known to be crucial to stress response such as NFkB and Nrf2. Spermine is catabolized by spermine oxidase (SMO) to produce spermidine, 3-aminopropanal (3-AP), and H₂O₂. Spermine and spermidine can both be catabolized by spermidine/spermine N¹-acetyltransferase (SSAT) to produce N¹-acetylspermine and N¹- acetylspermidine, which can then serve as substrates for N¹-acetylpolyamine oxidase (APAO), which produces either spermidine or putrescine, respectively, along with 3-acetoaminopropanal (3-AAP) and H₂O₂. These reactive aldehydes and H₂O₂ are capable of damaging cellular machinery, lipids, and DNA, leading to cellular dysfunction, apoptosis, or damage that may lead to carcinogenesis. Polyamines have many crucial roles in the cell and perturbance of the polyamine pool and loss of the higher polyamines through catabolism or export can also disrupt normal function and may contribute to the progression of disease.