LYSOPHOSPHATIDIC ACID STIMULATES PHOSPHOLIPASE-D ACTIVITY AND CELL-PROLIFERATION IN PC-3 HUMAN PROSTATE-CANCER CELLS

Phospholipase D (PLD) is activated in mammalian cells in response to a variety of growth factors and may play a role in cell proliferation. Lysophosphatidic acid (LPA) is a bioactive metabolite potentially gene rated as a result of PLD activation. Two human prostate cancer cell li nes, PC-3 and LNCaP, express membrane PLD activity. The effects of LPA on PLD activity and proliferation were examined in PC-3 cells, which express hPLD1a/1b. Phorbol 12-myristate 13-acetate (PMA) induced a pro longed activation of PLD, as detected in both intact cells and membran es. LPA induced a transient activation of PLD that was maximal by 10 m inutes. The EC50 for LPA-induced PLD activation was approximately 1 mu M. Pertussis toxin did not inhibit activation of PLD by LPA or PMA. R o-31-8220 and bisindolylmaleimide I, inhibitors of protein kinase C, b locked activation by PLD by both PMA and LPA. PMA-induced activation o f PLD did not appear to require translocation of PLDs from cytosol to membrane. LPA stimulated proliferation of PC-3 cells with an EC50 of a pproximately 0.2 mu M; this response was not inhibited by pertussis to xin. Perillyl alcohol, an anti-cancer drug, reversibly inhibited proli feration in response to either serum or LPA but did not inhibit activa tion of PLD by PMA or LPA. These data establish that LPA activates PLD and stimulates proliferation via G(i)-independent pathways in a human prostate cancer cell line. (C) 1998 Wiley-Liss, Inc.