LPA Receptor

Lysophosphatidic acid (LPA) consists of an acyl chain at the sn-1 (or sn-2) position of a glycerol backbone and a phosphate head group.  LPA activates at least six G-coupled protein receptors (LPA1–6) stimulating different signaling pathways through heterotrimeric G proteins such as Gi/0, G12/13, Gq/11, and Gs. The lysophosphatidic acid (LPA) is a lipid acting at the intersection of fibrosis and cancer development. LPA's pro-oncogenic (pro-proliferative, pro-angiogenic, anti-apoptotic, and pro-migration / invasion properties have been recently evidenced.  Increased secretion of LPA can be triggered by tissue damage (including surgery, chemotherapy and radiation therapy) and/or by chronic inflammation. In parallel of its pro-fibrotic activity, LPA has also been repeatedly described as an oncogenic promoter, responsible of tumour initiation, growth, and metastasis. LPA could stimulate production of VEGF, interleukine-8 (IL-8) and urokinase plasminogen activator (uPA) in ovarian cancer cells, enhancing hyper-vascularisation processes finally leading to metastases. 
LPAR1-4 stimulate the mitogenic pathway Ras-Ras-Raf-MEK-ERK pathway, and the pro-survival PI3K pathway. LPAR1-3 and LPAR5 stimulate the invasion/migration thought the activation of the Rho pathway. The Rac Pathway, also involved in invasion/migration, can be stimulated by LPAR1-4 as well. In vitro, LPA significantly increased ovarian cancer cell invasion, partly through the down-regulation of invasion negative regulators (tissue inhibitor of metalloproteinases (TIMPs)). In vivo, LPA stimulated ovarian tumour metastasis, but this phenomenon could be significantly inhibited using an inhibitor of PI3K (an effector in the LPA signalling pathway).


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