Polyamines and Cell Kinetic Behavior Apoptosis Proliferation of Prostatic Cells

Prostate growth depends on the balance between death (apoptosis) and proliferation of prostatic cells. To investigate the role of polyamine metabolism in prostatic growth, we have monitored the levels of polyamines, as well as the activities of the polyamine biosynthetic enzyme, ODC, and the polyamine-catabolizing enzyme, Spd/Spm acetyl-transferase (SSAT), in castration-induced regression and testosterone-stimulated regrowth of the rat prostate.

Before castration, both proliferation rate and apoptotic rate in the glandular prostatic tissue were less than 2%. In the first hours after castration, the apoptotic rate increased, reaching a maximum level of 15 to 20% after 2 d (Fig. 1A). Concomitantly, ODC activity (Fig. 1B) and polyamine levels (Fig. 1C) dramatically decreased, whereas SSAT activity progressively increased in the prostatic tissue (Fig. 1B). Regeneration of the prostate after suppletion of androgens coincided with a marked increase in ODC activity and recovery of polyamine concentrations to normal limits (Fig. 1A,C, right side). The effect of androgen/suppletion on prostate cell kinetics and polyamine parameters was notably less dramatic in the dorsolateral lobe of the prostate compared with the ventral lobe (results not shown).

Much ambiguity exists on the role of ODC in apoptosis because ODC activity is reported to be increased, decreased, or unchanged depending on the apoptotic stimulus or cell system used (seerefs. 18 and 19, and references herein). Remarkably, in most of these studies, ODC increases early during apoptosis but eventually polyamine levels mostly decreased. Several studies imply, however, that the increase in ODC activity is merely a trophic response to stress or is even just an epiphenomenon (see ref. 18 and references herein). The inability of ODC to maintain elevated polyamine levels may be owing to a precocious degradation of ODC during the cell death process. Proteolytic degradation of ODC is regulated by a unique protein, the so-called antizyme (AZ), which binds to ODC and facilitates its breakdown by the cytosolic 26S proteosome. In our recent study on the localization of ODC and AZ, we found that treatment of prosta-tic cancer cells with 1 mM putrescine resulted in nuclear induction of AZ that colocal-ized with a fusion protein of ODC conjugated with green fluorescent protein (GFP) (20). Consistent with this is that the proteolytic breakdown observed during apoptosis mostly affects proteins needed for cell cycle and survival. Because polyamines are critically involved in cell-cycle control, ODC may be one of the proteins that are degraded by apoptosis-related proteases. No evidence has yet been found for the proteolysis of ODC by caspases. However, a potential cleavage site (YVAD) for caspases is present in ODC in most animals. Interestingly, the amino acid sequence of the very stable ODC of Trypanosoma brucei contains HVAD, a site less vulnerable to caspase-mediated proteo-lysis. It is therefore tempting to speculate that ODC is a potential caspase target.

Concomitant to castration-induced apoptosis, SSAT activity progressively increased in the prostatic tissue (Fig. 1B). We observed a similar, relatively late induction of SSAT in calcium-ionophore-induced apoptosis of prostate cancer cells (21). These results suggest that polyamine catabolism is associated with the later stages of apoptosis.

Increased expression of SSAT during apoptosis has also been reported in other studies (see ref. 19 and references herein) suggesting that stimulation of polyamine catabo-lism is a general cellular response in cell death. Apoptosis induced by polyamine analogs has been associated with highly increased SSAT levels (see Chapters 12 and 15).

The link between SSAT induction and apoptosis may actually be associated with the action of another polyamine catabolic enzyme, polyamine oxidase, which oxidizes acetylated polyamines generated by SSAT and releases toxic byproducts, such as hydrogen peroxide and aldehydes (see Chapter 12), which in turn, could trigger the apoptotic process.

Fig. 1. Apoptosis and proliferation index, and parameters of polyamine homeostasis in castration-induced involution and testosterone-induced regrowth of the rat ventral prostate. (A) The apoptosis index was expressed as the fraction of in situ nick translation (ISNT)-positive glandular epithelial cells, as well as the proliferation index as the fraction of BrdU positive cells. (B) Activities of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC) and the polyamine catabolic enzyme Spd/Spm W'-acetyltransferases (SSAT). (C) Concentrations of putrescine (Put), spermidine (Spd), and spermine (Spm).

Fig. 1. Apoptosis and proliferation index, and parameters of polyamine homeostasis in castration-induced involution and testosterone-induced regrowth of the rat ventral prostate. (A) The apoptosis index was expressed as the fraction of in situ nick translation (ISNT)-positive glandular epithelial cells, as well as the proliferation index as the fraction of BrdU positive cells. (B) Activities of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC) and the polyamine catabolic enzyme Spd/Spm W'-acetyltransferases (SSAT). (C) Concentrations of putrescine (Put), spermidine (Spd), and spermine (Spm).

Was this article helpful?

0 0
Healthy Chemistry For Optimal Health

Healthy Chemistry For Optimal Health

Thousands Have Used Chemicals To Improve Their Medical Condition. This Book Is one Of The Most Valuable Resources In The World When It Comes To Chemicals. Not All Chemicals Are Harmful For Your Body – Find Out Those That Helps To Maintain Your Health.

Get My Free Ebook


Post a comment