title: 14-3-3sigma, a p53 regulator, suppresses tumor growth of nasopharyngeal carcinoma.
abstract: The 14-3-3sigma gene product, up-regulated by p53 in response to DNA damage, is involved in cell-cycle checkpoint control and is a human cancer epithelial marker down-regulated in various tumors. However, its role and function have not been established in nasopharyngeal carcinoma (NPC), a tumor of epithelial origin. Recently, we found that 14-3-3sigma interacts with p53 in response to DNA damage and stabilizes the expression of p53. In addition, we also showed that overexpression of 14-3-3sigma inhibits oncogene-activated tumorigenicity. In the present study, we investigated the tumor-suppressive role of 14-3-3sigma in NPC cells. We found that there is a failure to up-regulate 14-3-3sigma in response to DNA damage in two NPC cell lines that have p53 mutation. We also found that 14-3-3sigma interacted with protein kinase B/Akt and negatively regulated the activity of Akt. Overexpression of 14-3-3sigma inhibited NPC cell growth and blocks DNA synthesis. Overexpression of 14-3-3sigma also led to inhibition of anchorage-independent growth of NPC cells. In addition, we found that 14-3-3sigma sensitized NPC cells to apoptosis induced by the chemotherapeutic agent 2-methoxyestradiol. Overexpression of 14-3-3sigma in both NPC cell lines reduced the tumor volume in nude mice, which could have significance for clinical application. These findings provide an insight into the roles of 14-3-3sigma in NPC and suggest that approaches that modulate 14-3-3sigma activity may be useful in the treatment of NPC.
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Box 79, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Huiling
authors.initials: H
authors.lastname: Yang
authors.forename: Ruiying
authors.initials: R
authors.lastname: Zhao
authors.forename: Mong-Hong
authors.initials: MH
authors.lastname: Lee
mesh_terms: D048948:14-3-3 Proteins; D000077584:2-Methoxyestradiol; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005092:Exonucleases / Q000235:genetics / Q000378:metabolism*; D005095:Exoribonucleases; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015533:Transcriptional Activation; D050257:Tubulin Modulators / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D050257:Tubulin Modulators; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; D000077584:2-Methoxyestradiol; D051057:Proto-Oncogene Proteins c-akt; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human