Phorbol 12-Myristate 13-Acetate Stimulates Lysophosphatidic Acid Secretion from Ovarian and Cervical Cancer Cells but Not from Breast or Leukemia Cells

Abstract

Lysophosphatidic acid (LPA) is present in ascites from patients with ovarian cancer. It stimulates calcium release and growth of ovarian cancer cells bothin vitroandin vivo.Recently, we found that LPA levels were significantly elevated in plasma from patients with ovarian cancer and other gynecological cancers. In contrast, LPA levels were not elevated in patients with breast cancer and leukemias. In view of this, we investigated whether gynecological cancer cells could produce LPA. LPA was extracted from the supernatant of cells culturedin vitroand purified by thin layer chromatography. After hydrolysis and transmethylation, the fatty acid derivatives were analyzed by gas chromatography. We found that the phorbol ester, phorbol 12-myristate 13-acetate (PMA), significantly stimulated the production of LPA in ovarian and cervical cancer cells. In contrast, a small or negligible amount of LPA was produced in breast cancer and leukemia cells upon PMA stimulation. This cell type specificity correlates with our values of plasma LPA, suggesting that gynecological tumor cells may be an important source of the elevated LPA noted in the plasma of patients with these cancers. The cytosolic PLA2(cPLA2)/Ca2+-independent PLA2(iPLA2) inhibitor, AACOCF3, inhibited 75.6% PMA-stimulated LPA secretion in ovarian cancer cells, suggesting a cPLA2/iPLA2activity was involved in LPA production from ovarian cancer cells.