Anti-tumor activity of ESX1 on cancer cells harboring oncogenic K-ras mutation.
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.
Nakajima
Junta
J
Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan.
Ishikawa
Susumu
S
Hamada
Jun-Ichi
J
Yanagihara
Masatomo
M
Koike
Takao
T
Hatakeyama
Masanori
M
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000628:therapy*; D005260:Female; D011905:Genes, ras; D015316:Genetic Therapy / Q000379:methods*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use; D012097:Repressor Proteins / Q000235:genetics; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
C432969:ESX1 protein, human; D018398:Homeodomain Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus