Prostate Apoptosis Response‐4 Mediates Trophic Factor Withdrawal‐Induced Apoptosis of Hippocampal Neurons

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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.