ELEVATED LEVELS AND MITOGENIC ACTIVITY OF LYSOPHOSPHATIDYLINOSITOL INK-RAS-TRANSFORMED EPITHELIAL-CELLS

In cell lines stably (KiKi) or reversibly (Ts) transformed by the k-ra s oncogene originated from a differentiated rat thyroid line (FRTL5 ce lls), k-ras-induced transformation has been associated with an increas ed phospholipase A(2) activity. Here we provide evidence that this enz ymic activity is phosphoinositide specific and leads to the formation of lysophosphatidylinositol. The levels of this lysolipid increased by 2-3-fold in ras-transformed cells (KiKi cells and Ts cells at the per missive temperature of 33 degrees C) as compared to differentiated cel ls (FRTL5) or to Ts cells maintained at 39 degrees C, i.e. at the temp erature where ras-p21, the product of the ras oncogene, is inactive. S ince another lysoderivative, lysophosphatidic acid, has been shown to be a mitogen, we have tested whether lysophosphatidylinositol could ha ve a similar activity on thyroid cells. Lysophosphatidylinositol (10-1 00 mu M) induced a 5-10-fold increase in [H-3]thymidine incorporation in both FRTL5 and KiKi cells, whereas lysophosphatidic acid was active only in differentiated cells. Lysophosphatidylinositol (approximate t o 25 mu M) and lysophosphatidic acid (50-100 mu M) acted synergistical ly with insulin in increasing [H-3]thymidine incorporation. Moreover, lysophosphatidylinositol at concentrations threefold higher than those found to be mitogenic, inhibited the activity of the GTPase-activatin g protein. We conclude that lysophosphatidylinositol is a mitogen that might play a role in the modulation of k-ras transformed cell prolife ration.