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.
Tanaka
Masamitsu
M
Department of Growth Factor Division, National Cancer Center Research Institute, Tokyo, Japan.
Kamata
Reiko
R
Yanagihara
Kazuyoshi
K
Sakai
Ryuichi
R
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