Development of p53 protein transduction therapy using membrane-permeable peptides and the application to oral cancer cells.
Recent studies suggest that several proteins can transverse biological membranes through protein transduction. The protein transduction domains of these proteins, 10-16 residues long, have been identified as critical domains for the protein transduction. Poly-arginine peptide also has the ability of protein transduction. Here, we show that the protein delivery system using 11 poly-arginine peptides (11R) is a powerful tool for the transduction of the biologically active tumor suppressor protein, p53, to suppress the proliferation of oral cancer cells. The 11R-fused p53 proteins (11R-p53) effectively penetrated across the plasma membrane of the cancer cells and translocated into the nucleus. The proteins induced the activity of the p21/WAF promoter and inhibited the proliferation of human oral cancer cells, in which the p53 gene was mutated. The effect was equivalent to that of the adenovirus-mediated p53 gene transduction system. Moreover, 11R-p53 enhanced the cisplatin-dependent induction of apoptosis of the cells. These data suggest that this protein transduction method may become a promising cancer therapy.
Takenobu
Toshihiko
T
Department of Physiology, Graduate School of Medicine and Dentistry, Okayama University, Okayama 700-8558, Japan.
Tomizawa
Kazuhito
K
Matsushita
Masayuki
M
Li
Sheng-Tian
ST
Moriwaki
Akiyoshi
A
Lu
Yun-Fei
YF
Matsui
Hideki
H
D021581:Active Transport, Cell Nucleus; D000256:Adenoviridae / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D008856:Microscopy, Fluorescence; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D010455:Peptides; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; C015462:polyarginine; D002945:Cisplatin