Regulation of Polyamine Biosynthetic Activity and Homeostasis as a Novel Antiproliferative Strategy

Abstract

Induction of polyamine biosynthetic activity and the subsequent increases in intracellular polyamine pools are well documented components of the proliferative response (reviewed in 1–3). Indeed, several lines of evidence clearly indicate that sustained polyamine biosynthesis is a critical component of cell growth and not simply a consequence of it (2,4). In many ways, the association of polyamines with cell growth and, in particular, the properties of the enzyme proteins themselves bear intriguing resemblance to proto-oncogenes and their encoded products. Two key biosynthetic enzymes, ornithine and S-adenosylmethionine decarboxylase (ODC and AdoMetDC, respectively), are extremely short-lived with half-lives of less than 1 hr, highly inducible and subject to sensitive regulatory control. Increases in their activities are invariably associated with the very early stages of cell growth and, somewhat less consistently, with tumor promotion (5,6). Although the most illustrative of the enzymes in this respect, ODC, has not been shown to have transforming capabilities, cells which overexpress the enzyme can be endowed with increased proliferative potential (7) and/or tissue invasiveness (8). Moreover, induction of the enzyme, like certain of the proto-oncogenes, is known to be critically important for initiating and sustaining cell proliferation.