Role of autotaxin and lysophosphatidate in cancer progression and resistance to chemotherapy and radiotherapy

Abstract

There is an accumulating body of evidence linking the secreted enzyme autotaxin (ATX) and its product lysophosphatidate (LPA) to tumor progression, metastasis and resistance to chemotherapy or radiotherapy. ATX achieves this mainly by converting the abundant lysophosphatidylcholine in the circulation to the potent bioactive signaling molecule, LPA. ATX is also bound to integrins on cell surfaces, which enables it to deliver LPA locally to at least eight G-protein-coupled receptors. These receptors activate a variety of signaling cascades, which stimulate cell division, survival and migration. Cancer cells also often show decreased expression of LPP-1 and -3, which both dephosphorylate extracellular LPA and also block its signaling downstream of receptor activation. This contributes to the hypersensitivity of cancer cells to the effects of LPA signaling, which coupled with increased ATX expression, promotes their metastasis and survival.