Prostate apoptosis response-4 mediates trophic factor withdrawal- induced apoptosis of hippocampal neurons: Actions prior to mitochondrial dysfunction and caspase activation

Sic L. Chan, Steven P. Tammariello, Steve Estus, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

Abstract

Prostate apoptosis response-4 (Par-4) is the product of a gene up- regulated in prostate cancer cells undergoing apoptosis. We now report that Par-4 mRNA and protein levels rapidly and progressively increase 4-24 h following trophic factor withdrawal (TFW) in cultured embryonic rat hippocampal neurons. The increased Par-4 levels follow an increase of reactive oxygen species, and precede mitochondrial membrane depolarization, caspase activation, and nuclear chromatin condensation/fragmentation. Pretreatment of cultures with 17β-estradiol, vitamin E, and uric acid largely prevented Par-4 induction and cell death following TFW, demonstrating necessary roles for oxidative stress and membrane lipid peroxidation in TFW- induced neuronal apoptosis. Par-4 antisense oligonucleotide treatment blocked Par-4 protein increases and attenuated mitochondrial dysfunction, caspase activation, and cell death following TFW. Collectively, our data identify Par-4 as an early and pivotal player in neuronal apoptosis resulting from TFW and suggest that estrogen and antioxidants may prevent apoptosis, in part, by suppressing Par-4 production.

Original languageEnglish (US)
Pages (from-to)502-512
Number of pages11
JournalJournal of Neurochemistry
Volume73
Issue number2
DOIs
StatePublished - 1999
Externally publishedYes

Keywords

  • Antisense oligodeoxynucleotide
  • Caspase
  • Estrogen
  • Free radical
  • Mitochondrial membrane depolarization
  • Uric acid
  • Vitamin E

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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