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Regulation of melanoma‐cell motility by the lipoxygenase metabolite 12‐(S)‐hete

Cellular motility, a prerequisite for metastasis of tumor cells, is affected by a 55‐kDa tumor‐cell‐secreted cytokine which influences the migration of the producing cells and is called autocrine motility factor (AMF). Previous studies indicated that AMF stimulates motility by binding to its receptor, a cell‐surface glycoprotein of 78 kDa (gp78), inducing its phosphorylation, activating a pertussis toxin (PT)‐sensitive G‐protein, and stimulating inositol metabolism. However, the intracellular signaling mechanisms which transduce and regulate the AMF motility response remain largely unknown. 12‐(S)‐HETE, a lipoxygenase metabolite 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 both AMF and 12‐(S)‐HETE is inhibited by protein kinase C inhibitors. Furthermore, perturbation of the AMF receptor stimulated endogenous biosynthesis of 12(S)HETE. These results suggest the existence of an “autocrine motility cycle” which influences melanoma cell motility by gp78 activation, and production of second messengers which affect the cytoskeletal architecture and expression of the AMF receptor itself.