Differential control of apoptosis by DJ-1 in prostate benign and cancer cells.
DJ-1 is a conserved protein reported to be involved in diverse cellular processes ranging from cellular transformation, control of protein-RNA interaction, oxidative stress response to control of male infertility, among several others. Mutations in the human gene have been shown to be associated with an autosomal recessive, early onset Parkinson's disease (PARK7). The present study examines the control of DJ-1 expression in prostatic benign hyperplasia (BPH-1) and cancer (PC-3) cell lines in which DJ-1 abundance differs significantly. We show that while BPH-1 cells exhibit low basal level of DJ-1 expression, stress-inducing agents such as H(2)O(2) and mitomycin C markedly increase the intracellular level of the polypeptide. In contrast, DJ-1 expression is relatively high in PC-3 cells, and incubation with the same cytotoxic drugs does not modulate further the level of the polypeptide. In correlation with the expression of DJ-1, both cytotoxic agents activate the apoptotic pathway in the prostatic benign cells but not in PC-3 cells, which are resistant to their action. We further demonstrate that incubation of BPH-1 cells with TNF-related-apoptosis-inducing-ligand/Apo-2L (TRAIL) also enhances DJ-1 expression and that TRAIL and H(2)O(2) act additively to stimulate DJ-1 accumulation but synergistically in the activation of the apoptotic pathway. Time-course analysis of DJ-1 stimulation shows that while DJ-1 level increases without significant lag in TRAIL-treated cells, there is a delay in H(2)O(2)-treated cells, and that the increase in DJ-1 abundance precedes the activation of apoptosis. Unexpectedly, over-expression of DJ-1 de-sensitizes BPH-1 cells to the action of apoptotic-inducing agents. However, RNA-interference-mediated silencing of DJ-1 expression results in sensitization of PC-3 cells to TRAIL action. These results are consistent with a model in which DJ-1 is involved in the control of cell death in prostate cell lines. DJ-1 appears to play a differential role between cells expressing a low but inducible level of DJ-1 (e.g., BPH-1 cells) and those expressing a high but constitutive level of the polypeptide (e.g., PC-3 cells).
Hod
Yaacov
Y
Prostate Cancer Research Center, Department of Urology, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, New York 11794-8093, USA. Yaacov.Hod@stonybrook.edu
D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D017931:DNA Primers; D015536:Down-Regulation / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D016685:Mitomycin / Q000494:pharmacology; D011467:Prostate / Q000166:cytology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D034741:RNA, Small Interfering / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D017931:DNA Primers; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016685:Mitomycin; D006861:Hydrogen Peroxide