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¹ Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center and Programs in ² Cancer Biology and ³ Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas

Requests for reprints: Mong-Hong Lee, The University of Texas M.D. Anderson Cancer Center, Box 79, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-794-1323; Fax: 713-792-6059. E-mail: mhlee{at}mdanderson.org

The 14-3-3 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 14-3-3 interacts with p53 in response to DNA damage and stabilizes the expression of p53. In addition, we also showed that overexpression of 14-3-3 inhibits oncogene-activated tumorigenicity. In the present study, we investigated the tumor-suppressive role of 14-3-3 in NPC cells. We found that there is a failure to up-regulate 14-3-3 in response to DNA damage in two NPC cell lines that have p53 mutation. We also found that 14-3-3 interacted with protein kinase B/Akt and negatively regulated the activity of Akt. Overexpression of 14-3-3 inhibited NPC cell growth and blocks DNA synthesis. Overexpression of 14-3-3 also led to inhibition of anchorage-independent growth of NPC cells. In addition, we found that 14-3-3 sensitized NPC cells to apoptosis induced by the chemotherapeutic agent 2-methoxyestradiol. Overexpression of 14-3-3 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 14-3-3 in NPC and suggest that approaches that modulate 14-3-3 activity may be useful in the treatment of NPC. [Mol Cancer Ther 2006;5(2):253–60]

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Note: M-H. Lee is a recipient of the Flemin and Davenport Research Award. The current address for H. Yang is Department of Pathophysiology, Zhongshan University, Guangzhou, China.

⁴ H.Y. Yang, et al. DNA damage-induced protein 14-3-3 inhibits PKB/Akt activation and suppresses Akt-activated cancer, Cancer Research, in press.

Received 9/30/05; revised 11/ 4/05; accepted 12/ 1/05.

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