Activation of a Ca2+- Mg2 -dependent endonuclease as an early event in castration-induced prostatic cell death

N. Kyprianou, H. F. English, John Tod Isaacs

Research output: Contribution to journalArticle

Abstract

Previous studies have demonstrated that castration-induced androgen withdrawal results in the fragmentation of prostatic DNA into nucleosomal oligomers, and this process comprises an early event in the activation of programmed cell death in the rat ventral prostate. This DNA fragmentation could be due to changes in the chromatin conformation increasing its sensitivity to preexisting nucleases and/or to increases in the activity of the nucleases themselves. However, comparative kinetic analysis of in vitro DNA fragmentation induced by exogenous nucleases did not reveal any differences in the sensitivity of prostatic chromatin between intact and castrated rats. In contrast to these negative findings, using [3H]DNA as an exogenous substrate, it was shown that within the first day following castration there was a twofold increase in a Ca2+-Mg2+-dependent nuclease activity without a concomitant increase in other nuclear nucleases. This Ca2+-Mg2+-dependent nuclease activation occurred coincidental with the initial increase in nuclear DNA fragmentation following castration and preceded the enhanced appearance of morphological changes characteristic of dying cells (i.e., apoptosis), as well as the major increase in prostatic DNA loss. These results suggest that castration-induced androgen deprivation leads to a sequential activation of a Ca2+-Mg2+-dependent nuclease leading to the fragmentation of the genome into discrete nucleosomal-sized fragments of DNA, subsequently followed by the fragmentation of the nucleus itself (i.e., apoptosis) and eventually with the complete digestion of the nucleosomal oligomers into component nucleotides (i.e., DNA loss). Since the castration-induced nuclease is dependent upon calcium ions for maximal activity, a potential role of intracellular calcium in the early events activating prostatic cell death was investigated. Acute disturbances in intracellular calcium homeostasis within the ventral prostate by means of a potent calcium influx blocker, nifedipine, simultaneous with castration, resulted in a significant delay in the biochemical and morphological changes associated with prostatic cell death (i.e., prostatic weight loss, prostatic DNA loss, and DNA fragmentation). These results point to a potential role of intracellular calcium levels in the mechanism of activation of castration-induced death of the androgen-dependent epithelial cells in the ventral prostate.

Original languageEnglish (US)
Pages (from-to)103-117
Number of pages15
JournalProstate
Volume13
Issue number2
StatePublished - 1988

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Endonucleases
Castration
Cell Death
DNA Fragmentation
Calcium
DNA
Androgens
Prostate
Chromatin
Apoptosis
Nifedipine
Weight Loss
Digestion
Homeostasis
Nucleotides
Epithelial Cells
Genome
Ions

ASJC Scopus subject areas

  • Urology

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Activation of a Ca2+- Mg2 -dependent endonuclease as an early event in castration-induced prostatic cell death. / Kyprianou, N.; English, H. F.; Isaacs, John Tod.

In: Prostate, Vol. 13, No. 2, 1988, p. 103-117.

Research output: Contribution to journalArticle

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abstract = "Previous studies have demonstrated that castration-induced androgen withdrawal results in the fragmentation of prostatic DNA into nucleosomal oligomers, and this process comprises an early event in the activation of programmed cell death in the rat ventral prostate. This DNA fragmentation could be due to changes in the chromatin conformation increasing its sensitivity to preexisting nucleases and/or to increases in the activity of the nucleases themselves. However, comparative kinetic analysis of in vitro DNA fragmentation induced by exogenous nucleases did not reveal any differences in the sensitivity of prostatic chromatin between intact and castrated rats. In contrast to these negative findings, using [3H]DNA as an exogenous substrate, it was shown that within the first day following castration there was a twofold increase in a Ca2+-Mg2+-dependent nuclease activity without a concomitant increase in other nuclear nucleases. This Ca2+-Mg2+-dependent nuclease activation occurred coincidental with the initial increase in nuclear DNA fragmentation following castration and preceded the enhanced appearance of morphological changes characteristic of dying cells (i.e., apoptosis), as well as the major increase in prostatic DNA loss. These results suggest that castration-induced androgen deprivation leads to a sequential activation of a Ca2+-Mg2+-dependent nuclease leading to the fragmentation of the genome into discrete nucleosomal-sized fragments of DNA, subsequently followed by the fragmentation of the nucleus itself (i.e., apoptosis) and eventually with the complete digestion of the nucleosomal oligomers into component nucleotides (i.e., DNA loss). Since the castration-induced nuclease is dependent upon calcium ions for maximal activity, a potential role of intracellular calcium in the early events activating prostatic cell death was investigated. Acute disturbances in intracellular calcium homeostasis within the ventral prostate by means of a potent calcium influx blocker, nifedipine, simultaneous with castration, resulted in a significant delay in the biochemical and morphological changes associated with prostatic cell death (i.e., prostatic weight loss, prostatic DNA loss, and DNA fragmentation). These results point to a potential role of intracellular calcium levels in the mechanism of activation of castration-induced death of the androgen-dependent epithelial cells in the ventral prostate.",
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AB - Previous studies have demonstrated that castration-induced androgen withdrawal results in the fragmentation of prostatic DNA into nucleosomal oligomers, and this process comprises an early event in the activation of programmed cell death in the rat ventral prostate. This DNA fragmentation could be due to changes in the chromatin conformation increasing its sensitivity to preexisting nucleases and/or to increases in the activity of the nucleases themselves. However, comparative kinetic analysis of in vitro DNA fragmentation induced by exogenous nucleases did not reveal any differences in the sensitivity of prostatic chromatin between intact and castrated rats. In contrast to these negative findings, using [3H]DNA as an exogenous substrate, it was shown that within the first day following castration there was a twofold increase in a Ca2+-Mg2+-dependent nuclease activity without a concomitant increase in other nuclear nucleases. This Ca2+-Mg2+-dependent nuclease activation occurred coincidental with the initial increase in nuclear DNA fragmentation following castration and preceded the enhanced appearance of morphological changes characteristic of dying cells (i.e., apoptosis), as well as the major increase in prostatic DNA loss. These results suggest that castration-induced androgen deprivation leads to a sequential activation of a Ca2+-Mg2+-dependent nuclease leading to the fragmentation of the genome into discrete nucleosomal-sized fragments of DNA, subsequently followed by the fragmentation of the nucleus itself (i.e., apoptosis) and eventually with the complete digestion of the nucleosomal oligomers into component nucleotides (i.e., DNA loss). Since the castration-induced nuclease is dependent upon calcium ions for maximal activity, a potential role of intracellular calcium in the early events activating prostatic cell death was investigated. Acute disturbances in intracellular calcium homeostasis within the ventral prostate by means of a potent calcium influx blocker, nifedipine, simultaneous with castration, resulted in a significant delay in the biochemical and morphological changes associated with prostatic cell death (i.e., prostatic weight loss, prostatic DNA loss, and DNA fragmentation). These results point to a potential role of intracellular calcium levels in the mechanism of activation of castration-induced death of the androgen-dependent epithelial cells in the ventral prostate.

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