RT Journal Article
SR Electronic
T1 <em>KiSS1</em> Metastasis Suppressor Gene Product Induces Suppression of Tyrosine Kinase Receptor Signaling to Akt, Tumor Necrosis Factor Family Ligand Expression, and Apoptosis
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1074
OP 1083
DO 10.1124/mol.108.054270
VO 75
IS 5
A1 Jean-Marc Navenot
A1 Nobutaka Fujii
A1 Stephen C. Peiper
YR 2009
UL http://molpharm.aspetjournals.org/content/75/5/1074.abstract
AB The powerful metastasis suppressor function of KiSS1 gene products has been demonstrated in both clinical studies and experimental models, but its mechanism is still incompletely understood. Studies on the antimetastatic function of KiSS1 and GPR54 largely focused on the autocrine inhibition of cell motility, despite experimental evidence of an alternative post-migratory effect. We showed previously that the activation of its cognate receptor GPR54 by kisspeptin-10 suppressed the capacity of the prometastatic chemokine receptor CXCR4 to induce chemotaxis in response to stromal cell derived factor 1 and abolished the activation of Akt by CXCR4. We demonstrate here that activation of GPR54 can also abolish the activation of Akt by the tyrosine kinase receptors for epidermal growth factor and insulin. The signaling of GPR54 was sufficient to trigger apoptosis in epithelial and lymphoid cell lines. Surprisingly, this phenomenon depended largely on the activation of extracellular signal-regulated kinase (ERK) rather than the inhibition of Akt. Activation of GPR54 resulted in the ERK-dependent expression of tumor necrosis factor-α and FasL in a lymphoid cell line, the latter being the main trigger of apoptosis. These data provide novel mechanisms relevant to a potential autocrine metastasis suppression effect of KiSS1 on GPR54-positive tumor cells. More importantly, they also establish an experimental basis for a paracrine mode of action by which kisspeptins suppress the metastatic potential of tumor cells lacking expression of the receptor, as observed in several animal models of metastasis. The action on stromal cells significantly broadens the clinical relevance of this metastasis suppressor. The American Society for Pharmacology and Experimental Therapeutics