Suppression of gastric cancer dissemination by ephrin-B1-derived peptide.
Interaction of the Eph family of receptor protein tyrosine kinases and their ligands, ephrin family members, induces bidirectional signaling through cell-cell contacts. High expression of B-type ephrin is associated with high invasion potential of tumors, and we previously observed that signaling through the C-terminus of ephrin-B1 mediates the migration and invasion of cells, and is involved in the promotion of carcinomatous peritonitis in vivo. Here we show that the intracellular introduction of a synthetic peptide derived from ephrin-B1 C-terminus blocks ephrin-B1 mediated signaling in scirrhous gastric cancer cells. Treatment of cancer cells with a fusion peptide consisting of HIV-TAT and amino acids 331-346 of ephrin-B1 (PTD-EFNB1-C) suppressed the activation of RhoA, mediated by the association of ephrin-B1 with an adaptor protein Dishevelled, and also inhibited extracellular secretion of metalloproteinase. Moreover, injection of PTD-EFNB1-C peptide into the peritoneal cavity of nude mice suppressed carcinomatous peritonitis of intraperitoneally transplanted scirrhous gastric cancer cells. These results indicate the possible application of ephrin-B1 C-terminal peptide to develop novel protein therapy for scirrhous gastric carcinoma, especially in the stage of tumor progression, including peritoneal dissemination.
Department of Growth Factor Division, National Cancer Center Research Institute, Tokyo, Japan.
Masamitsu
M
Tanaka
Reiko
R
Kamata
Kazuyoshi
K
Yanagihara
Ryuichi
R
Sakai
D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D036387:Ephrin-B1 / Q000037:antagonists & inhibitors*; D006801:Humans; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000627:therapeutic use*; D010534:Peritoneal Neoplasms / Q000517:prevention & control; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000077022:Survivin; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000627:therapeutic use*
D051017:Apoptosis Regulatory Proteins; D036387:Ephrin-B1; C512124:HIV-TAT-survivin (T34A) protein; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D000077022:Survivin; D054322:tat Gene Products, Human Immunodeficiency Virus; D020784:Matrix Metalloproteinase 8; D020742:rhoA GTP-Binding Protein