14-3-3sigma is down-regulated in human prostate cancer.
The 14-3-3sigma is a negative regulator of the cell cycle, which is induced by p53 in response to DNA damage. It has been characterized as an epithelium-specific marker and down-regulation of the protein has been shown in breast cancers, suggesting its tumor-suppressive activity in epithelial cells. Here we demonstrate that 14-3-3sigma protein is down-regulated in human prostate cancer cell lines, LNCaP, PC3, and DU145 compared with normal prostate epithelial cells. Immunohistochemical analysis of primary prostate cells shows that the expression of 14-3-3sigma protein is epithelial cell-specific. Among prostate pathological specimens, > 95% of benign hyperplasia samples show significant and diffuse immunostaining of 14-3-3sigma in the cytoplasm whereas < 20% of carcinoma samples show positive staining. In terms of mechanisms for the down-regulation of 14-3-3sigma in prostate cancer cells, hypermethylation of the gene promoter plays a causal role in LNCaP cells as 14-3-3sigma mRNA level was elevated by 5-aza-2'-deoxycytidine demethylating treatment. Intriguingly, the proteasome-mediated proteolysis is responsible for 14-3-3sigma reduction in DU145 and PC3 cells, as 14-3-3sigma protein expression was increased by treatment with a proteasome inhibitor MG132. Furthermore, tumor necrosis factor-related apoptosis-inducing ligand enhances 14-3-3sigma gene and protein expression in DU145 and PC3 cells. These data suggest that 14-3-3sigma expression is down-regulated during the neoplastic transition of prostate epithelial cells.
Urano
Tomohiko
T
Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Takahashi
Satoru
S
Suzuki
Takashi
T
Fujimura
Tetsuya
T
Fujita
Masayo
M
Kumagai
Jinpei
J
Horie-Inoue
Kuniko
K
Sasano
Hironobu
H
Kitamura
Tadaichi
T
Ouchi
Yasuyoshi
Y
Inoue
Satoshi
S
D048948:14-3-3 Proteins; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015536:Down-Regulation; D005092:Exonucleases / Q000235:genetics / Q000378:metabolism*; D005095:Exoribonucleases; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008745:Methylation; D009097:Multienzyme Complexes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D048948:14-3-3 Proteins; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex