Anti-tumor activity of antizyme which targets the ornithine decarboxylase (ODC) required for cell growth and transformation

Abstract

Cell proliferation and transformation induced by growth factor stimulation or by carcinogens, viruses, or oncogenes are characterized by an associated increase in polyamine levels, which is mediated by increased polyamine biosynthesis and enhanced uptake of polyamines. Polyamine biosynthesis is catalyzed particularly, in the level of ornithine decarboxylase (ODC). The elevation of cellular polyamine levels on the other hand accelerates the induction of ornithine decarboxylase antizyme (antizyme), which is involved not only in ODC-degradation, but in the negative regulation of polyamine transport. Taking advantage of these characteristics of antizyme, the potential of antizyme as a factor having anti-cell growth and anti-tumor activity was investigated. We show that antizyme can induce cell death associated with a rapid decline of intracellular polyamine contents. The possible anti-tumor activities of ectopically expressed antizyme were tested in p21H-ras (Val 12)-transformed NIH3T3 cells and several human malignant cell lines including a line with loss of p53 expression, and they were shown to be as sensitive as nontransformed NIH3T3 cells in vitro. The in vivo antitumor activity was also tested using nude mice inoculated with H-ras transformed NIH3T3 cells that had been transfected with inducible antizyme expression vector and the results showed that antizyme expression in vivo blocks tumor formation in these mice. These results suggest that ectopic antizyme expression is of possible therapeutic bene®t in the treatment of cancer, which is mediated by ODC inactivation and intracellular polyamine depletion.

A Definitive Role of Ornithine Decarboxylase in Photocarcinogenesis

“…18 Growth induction of normal cells is known to be accompanied by a rapid transient increase in ODC activity. 33,34 Cell transformation induced by oncogenes such as v-src, neu, and ras has been shown to be associated with constitutively elevated ODC activity. 18,[35][36][37] The up-regulation of ODC is considered essential for cell transformation.…”

Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification

“…Since elevated ODC activity is associated with most forms of human malignancies (Gerner and Meyskens, 2004), it was suggested early on that antizyme 1 may function as a tumor suppressor. Supporting this hypothesis, it has been shown that antizyme 1 overexpression leads to cell cycle arrest, apoptosis and reduced cell proliferation in vitro, (Iwata et al, 1999;Koike et al, 1999) and inhibits tumor growth in several mouse models in vivo (Iwata et al, 1999;Tsuji et al, 2001;Fong et al, 2003).…”

Antizyme1 mediates AURKAIP1-dependent degradation of Aurora-A

“…Higher levels of Az have been shown to be associated with decreased cell proliferation and hence Az has been considered as a tumor-suppressor (Iwata et al, 1999;Fong et al, 2003). It is tempting to speculate that the negative regulation of the oncogenic Aurora-A could be one of the manifestations of its tumor-suppressor functions.…”

“…Increased polyamines and ODC activities are associated with many human malignancies (Gerner and Meyskens, 2004). As a negative regulator of ODC and thus polyamine levels, overexpression of Az leads to cell-cycle arrest, apoptosis (Iwata et al, 1999;Koike et al, 1999) and inhibition of tumor growth in in vivo mouse models (Feith et al, 2001;Fong et al, 2003). Az increases ODC degradation by enhancing ODC association with proteasome, rather than accelerating the rate of proteasomal processing (Zhang et al, 2003).…”