Abstract
Prostate cancer cells are generally resistant to apoptosis by conventional therapy. During a search for molecules that may overcome prostate cancer cell survival mechanisms, we identified the prostate apoptosis response-4 (Par-4) gene. Par-4 induced apoptosis of selective prostate cancer cells PC-3, DU-145, and TSU-Pr and caused tumor regression by inhibition of NF-kappaB activity and cell membrane trafficking of Fas and FasL that leads to the activation of the Fas-Fas-associated death domain-caspase-8 pro-death pathway. Neither Fas pathway activation alone nor inhibition of NF-kappaB activity with IkappaB-super repressor was sufficient to induce apoptosis of prostate cancer cells. Coregulation of these two pathways was essential and sufficient for Par-4 to induce apoptosis. On the other hand, prostate cancer cells LNCaP or normal prostatic epithelial cells that were resistant to apoptosis by Par-4 did not show Fas or FasL trafficking. These findings identify a mechanism of apoptosis by Par-4 and suggest that Par-4 may have therapeutic potential.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Androgens / physiology
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Animals
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Apoptosis / genetics
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cell Membrane / metabolism
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Fas Ligand Protein
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Humans
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Intracellular Signaling Peptides and Proteins*
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Male
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / physiology*
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Mice
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / physiology
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Neoplasms, Hormone-Dependent / genetics
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Neoplasms, Hormone-Dependent / pathology
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PTEN Phosphohydrolase
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Phosphoric Monoester Hydrolases / antagonists & inhibitors
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / physiology
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / pathology*
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Prostatic Neoplasms / therapy
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Proto-Oncogene Proteins c-bcl-2 / physiology
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Signal Transduction / physiology
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Transcription, Genetic / physiology
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Transfection
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Tumor Suppressor Protein p53 / physiology
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Tumor Suppressor Proteins*
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Xenograft Model Antitumor Assays
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bcl-X Protein
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fas Receptor / metabolism
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fas Receptor / physiology*
Substances
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Androgens
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Apoptosis Regulatory Proteins
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BCL2L1 protein, human
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Bcl2l1 protein, mouse
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Carrier Proteins
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FASLG protein, human
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Fas Ligand Protein
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Fasl protein, mouse
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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NF-kappa B
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Proto-Oncogene Proteins c-bcl-2
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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bcl-X Protein
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fas Receptor
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prostate apoptosis response-4 protein
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human