REGULATION OF MELANOMA-CELL MOTILITY BY THE LIPOXYGENASE METABOLITE 12-(S)-HETE

Cellular motility, a prerequisite for metastasis of tumor cells, is af fected by a 55-kDa tumor-cell-secreted cytokine which influences the m igration of the producing cells and is called autocrine motility facto r (AMF). Previous studies indicated that AMF stimulates motility by bi nding to its receptor, a cell-surface glycoprotein of 78 kDa (gp78), i nducing its phosphorylation, activating a pertussis toxin (PT)-sensiti ve G-protein, and stimulating inositol metabolism. However, the intrac ellular signaling mechanisms which transduce and regulate the AMF moti lity response remain largely unknown. 12-(S)-HETE, a lipoxygenase meta bolite of arachidonic acid which affects the cytoskeletal architecture of murine melanoma cells, also stimulates cell motility independently of PT-sensitive G-proteins and up-regulates gp78 surface expression. 12-(S)-HETE induces the phosphorylation of gp78 in a manner analogous to AMF and the motility response of these murine melanoma cells to bot h AMF and 12-(S)-HETE is inhibited by protein kinase C inhibitors. Fur thermore, perturbation of the AMF receptor stimulated endogenous biosy nthesis of 12(S)HETE. These results suggest the existence of an ''auto crine motility cycle'' which influences melanoma cell motility by gp78 activation, and production of second messengers which affect the cyto skeletal architecture and expression of the AMF receptor itself. (C) 1 993 Wiley-Liss, Inc.