Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor.
Metastasis is a major cause of death in cancer patients and involves a multistep process including detachment of cancer cells from a primary cancer, invasion of surrounding tissue, spread through circulation, re-invasion and proliferation in distant organs. KiSS-1 is a human metastasis suppressor gene, that suppresses metastases of human melanomas and breast carcinomas without affecting tumorigenicity. However, its gene product and functional mechanisms have not been elucidated. Here we show that KiSS-1 (refs 1, 4) encodes a carboxy-terminally amidated peptide with 54 amino-acid residues, which we have isolated from human placenta as the endogenous ligand of an orphan G-protein-coupled receptor (hOT7T175) and have named 'metastin'. Metastin inhibits chemotaxis and invasion of hOT7T175-transfected CHO cells in vitro and attenuates pulmonary metastasis of hOT7T175-transfected B16-BL6 melanomas in vivo. The results suggest possible mechanisms of action for KiSS-1 and a potential new therapeutic approach.
Ohtaki
T
T
Pharmaceutical Discovery Research Division, Takeda Chemical Industries Ltd, Wadai 10, Tsukuba, Ibaraki 300-4293, Japan. Ohtaki_Tetsuya@takeda.co.jp
Shintani
Y
Y
Honda
S
S
Matsumoto
H
H
Hori
A
A
Kanehashi
K
K
Terao
Y
Y
Kumano
S
S
Takatsu
Y
Y
Masuda
Y
Y
Ishibashi
Y
Y
Watanabe
T
T
Asada
M
M
Yamada
T
T
Suenaga
M
M
Kitada
C
C
Usuki
S
S
Kurokawa
T
T
Onda
H
H
Nishimura
O
O
Fujino
M
M
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D059648:Kisspeptins; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
C106628:KISS1 protein, human; C491407:Kiss1 protein, mouse; C491406:Kiss1 protein, rat; D059648:Kisspeptins; D008024:Ligands; D010455:Peptides; D011506:Proteins; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D019204:GTP-Binding Proteins