Different induction of LPA receptors by chemical liver carcinogens regulates cellular functions of liver epithelial WB‐F344 cells

Abstract

Lysophosphatidic acid (LPA) signaling via LPA receptors (LPA to LPA ) mediates a variety of cellular functions, including cell motility. In the present study, we investigated the effects of LPA receptors on cell motile activity during multi-stage hepatocarcinogenesis in rat liver epithelial WB-F344 cells treated with chemical liver carcinogens. Cells were treated with a initiator (N-nitrosodiethylamine (DEN)) and three promoters (phenobarbital (PB), okadaic acid (OA) and clofibrate) every 24 h for 2 days. Cell motile activity was elevated by DEN, correlating with Lpar3 expression. PB, OA, and clofibrate elevated Lpar1 expression and inhibited cell motile activity. To evaluate the effects of long-term treatment on cell motility, cells were treated with DEN and/or PB for at least 6 months. Lpar3 expression and cell motile activity were significantly elevated by the long-term DEN treatment with or without further PB treatment. In contrast, long-term PB treatment with or without further DEN elevated Lpar1 expression and inhibited cell motility. When the synthesis of extracellular LPA was blocked by a potent ATX inhibitor S32826 before cell motility assay, the cell motility induced by DEN and PB was markedly suppressed. These results suggest that activation of the different LPA receptors may regulate the biological functions of cells treated with chemical carcinogens. © 2015 Wiley Periodicals, Inc.

Role of autotaxin in cancer stem cells

“…ONO-8430506, a tetrahydrocarboline derivative and ATX inhibitor, has been used to suppress plasma ATX activity in mice [110]. In another study, S32826, a benzyl phosphonic acid derivative ATX inhibitor, was used to reduce chemical liver carcinogenesis [111]. In other studies, a-bromophosphonates (BrP-LPA), which are lipid-mimetic ATX inhibitors and pan-antagonists of LPA1-3 receptors, were used to reduce breast tumor growth in orthotopic xenograft models [112] and lung cancer metastasis in nude mice [113].…”