title: Motif-programmed artificial protein induces apoptosis in several cancer cells by disrupting mitochondria.
abstract: By combinatorially assembling two natural motifs, respectively, associated with protein transduction (PTD) and induction of apoptosis (BH3), we previously synthesized an artificial protein (#284) that is taken up into cells, where it induces apoptosis. Here we used cluster analysis of GI(50) (average concentration required for 50% growth inhibition), as well as immunohistochemical and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling analyses to further characterize the capacity of #284 to induce apoptosis in a panel of 39 cancer cell lines. Our results showed that #284 preferentially inhibited the growth of several cancer cells with a GI(50) of approximately 5 microM, which is in the range of conventional anticancer drugs such as cisplatin and etoposide. In breast cancer HBC-4 cells, #284 caused mitochondrial aggregation and induced apoptosis in a BH3 motif-dependent manner. Moreover, transfection of the artificial gene that encodes #284 led to effective expression of the artificial protein within cells, which in turn caused apoptosis at a level similar to that seen in naturally occurring apoptosis inducers, Noxa/Bax transfectants. These findings suggest that synthetic proteins created by reprogramming peptide motifs have the potential to serve as novel agents useful in the treatment of cancer.
authors.affiliation: Department of Protein Engineering, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
authors.forename: Hirohide
authors.initials: H
authors.lastname: Saito
authors.forename: Tamiko
authors.initials: T
authors.lastname: Minamisawa
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Shiba
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D017209:Apoptosis; D045744:Cell Line, Tumor; D006801:Humans; D020287:In Situ Nick-End Labeling; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D015202:Protein Engineering; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D011506:Proteins; D011993:Recombinant Fusion Proteins; C528189:artificial protein 284