RELEASE OF THE MITOGEN LYSOPHOSPHATIDYLINOSITOL FROM H-RAS-TRANSFORMED FIBROBLASTS - A POSSIBLE MECHANISM OF AUTOCRINE CONTROL OF CELL-PROLIFERATION

Lysophosphatidylinositol (LysoPtdIns) is formed by a constitutively-ac tive phosphoinositide-specific phospholipase A(2) in Ras-transformed c ells and can stimulate cell proliferation. To evaluate whether LysoPtd Ins could function as an autocrine modulator of cell growth, we examin ed whether LysoPtdIns can be released in the medium of Ras-transformed FRT-Fibro fibroblasts and thyroid cells. Here, we report that LysoPtd Ins accumulates in the extracellular space of these lines and reaches levels up to tenfold higher than in the case of normal cells. Moreover , the ionophore A23187 increased the levels of the lysolipid in the ex tracellular medium. Extracellular LysoPtdIns was rapidly hydrolyzed to inositol 1:2-cyclic phosphate. LysoPtdIns induced thymidine incorpora tion in FRT-Fibro Ha-Ras fibroblasts, whereas inositol cyclic 1:2-cycl ic phosphate did not affect cell growth per se, nor did it interfere w ith the LysoPtdIns mitogenic activity. We hypothesize that in Ras-tran sformed fibroblasts the formation and release of LysoPtdIns may functi on as an autocrine mechanism that participates in the Ras-dependent st imulation of cell growth.