Regulation of cell proliferation and migration by phosphatidic acid and ceramide 1-phosphate. Implication in lung cancer and inflammation

Abstract

According to the World Health Organization (WHO), chronic inflammatory lung diseases, includingasthma, COPD, fibrosis, or lung cancer are among the major causes of death Worldwide. Althoughthese are subjects of intense investigation, progress on the therapeutic procedures to treat thesediseases is not as fast as one might desire. Hence, novel therapeutic strategies are urgently needed toeffectively treat lung cancer and inflammation. In the present thesis, we demonstrate thatphosphatidic acid (PA), a bioactive glycerophospholipid, is implicated in the regulation of myoblastproliferation and lung cancer cell migration through mechanisms involving interaction of thephospholipid with LPA receptors and subsequent activation of key signaling pathways, namely theMAP kinases ERK1-2, p38 and JNK, as well as the JAK2/STAT3 and PI3K/Akt/mTOR pathways.In addition, we show that ceramide 1-phosphate (C1P) inhibits PA-stimulated lung cancer cellmigration, and that it reduces cigarette smoke-induced human eosinophil migration. The latteraspects point to an antitumorigenic action of C1P in lung cancer and an anti-inflammatory effect ofC1P in inflammatory diseases that accompany eosinophil accumulation, such as asthma or COPD.The results of this thesis suggest that therapies based on the use of C1P or C1P analogues may beuseful for treatment of lung cancer and lung inflammatory diseases.