Activation of a Ca2+−Mg2+‐dependent endonuclease as an early event in castration‐induced prostatic cell death
- 1 January 1988
- journal article
- Published by Wiley in The Prostate
- Vol. 13 (2), 103-117
- https://doi.org/10.1002/pros.2990130203
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 programed 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+‐M2+‐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.Keywords
This publication has 24 references indexed in Scilit:
- Intracellular Ca2+ and cell injury: A paradoxical role of Ca2+ in complement membrane attackCell Calcium, 1986
- Death and the cellImmunology Today, 1986
- Androgen‐repressed messages in the rat ventral prostateThe Prostate, 1986
- Antagonistic effect of androgen on prostatic cell deathThe Prostate, 1984
- Successive waves of apoptosis in the rat prostate after repeated withdrawal of testosterone stimulationPathology, 1984
- A qualitative analysis of acidic proteins associated with regressing, growing, or dividing rat ventral prostate cellsThe Prostate, 1983
- The genetic program of cell death. hypothesis and some applications: Transformation, carcinogenesis, ageingJournal of Theoretical Biology, 1982
- The role of calcium in cell deathLife Sciences, 1981
- Calcium and A23187-induced cytolysis of mouse thymocytesBiochemical and Biophysical Research Communications, 1980
- The effects of testosterone, 5α-dihydrotestosterone and adenosine 3′,5′-monophosphate on cell proliferation and differentiation in RAT prostateBiochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis, 1973