Laminin-alpha1-chain sequence Leu-Gln-Val-Gln-Leu-Ser-Ile-Arg (LQVQLSIR) enhances murine melanoma cell metastases.
We earlier screened overlapping synthetic peptides from the globular domain of the laminin alpha1 chain to identify active sites for cell attachment. We report here that one of the active cell-adhesion peptides, AG-73 (Arg-Lys-Arg-Leu-Gln-Val-Gln-Leu-Ser-Ile-Arg-Thr; RKRLQVQLSIRT) causes B16F10 murine melanoma cells to metastasize to the liver, a site not normally colonized by these cells. Increases in liver metastases and in lung colonization are observed in immune-deficient beige/nude/xid and in C57Bl/6 mice with this peptide. This metastatic activity was observed with i.v. and with i.p. peptide injections, regardless of tumor cell or of peptide-injection times. In vitro, the AG-73 peptide enhances tumor cell adhesion, migration, invasion, and gelatinase production, and blocks laminin-1-mediated cell migration. AG-73 was found to significantly inhibit cell adhesion to a proteolytic laminin-1 fragment, E3, containing the AG-73 sequence. Cell attachment to AG-73, the E3 fragment, and laminin-1 involved cation-dependent receptors. We report that a laminin peptide has the novel and unexpected activity of causing B16F10 melanoma cells, a lung selected cell line, to metastasize to the liver. The minimal active sequence of AG-73, LQVQLSIR, could be one of the most important biologically active sites of laminin-1, especially in promotion of the malignant phenotype. Activation of the malignant phenotype by this peptide provides a significant new model for understanding metastatic mechanisms.
National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892-4370, USA.
W H
WH
Kim
M
M
Nomizu
S Y
SY
Song
K
K
Tanaka
Y
Y
Kuratomi
H K
HK
Kleinman
Y
Y
Yamada
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D018093:Gelatinases / Q000378:metabolism; D007797:Laminin / Q000494:pharmacology* / Q000502:physiology; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D008546:Melanoma, Experimental / Q000201:enzymology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology* / Q000502:physiology
C105786:AG 73; D007797:Laminin; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D018093:Gelatinases