Anti-tumor activity of ESX1 on cancer cells harboring oncogenic K-ras mutation

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• 作者：Junta Nakajima ; Susumu Ishikawa ; Jun-Ichi Hamada ; Masatomo Yanagihara ; Takao Koike ; Masanori Hatakeyama
• 关键词：ESX1 ; Oncogenic K-ras ; Transcriptional repressor ; TAT-fusion protein ; Molecular targeting therapy
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2008
• 期刊代码：159_0006291x
• 类别：bio
• 出版时间：23 May 2008
• 卷：370
• 期：1
• 页码：189-194
• 文件大小：305 K

摘要

Human ESX1 is a 65-kilodalton (kDa) paired-like homeoprotein that is proteolytically processed into N-terminal 45-kDa and C-terminal 20-kDa fragments. The N-terminal ESX1 fragment, which contains the homeodomain, localizes to the nucleus and represses mRNA transcription from the K-ras gene. When we inoculated human colorectal carcinoma HCT116 constitutive expressing N-terminal region of ESX1 (N-ESX1) into nude mice, transfectant cells uniformly showed decreased tumor-forming activity compared with that of the parental cells. Furthermore, pretreatment of HCT116 carcinoma cells with a fusion protein consisting of N-ESX1 and the protein-transduction domain derived from the human immunodeficiency virus type-1 TAT protein gave rise to a dramatic reduction in the tumorigenicity of HCT116 cells in nude mice. Our results provide first in vivo evidence for the molecular targeting therapeutic application of the K-ras repressor ESX1, especially TAT-mediated transduction of N-ESX1, in the treatment of human cancers having oncogenic K-ras mutations.