Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo
MGKB is the recipient of a Vanier Canada Graduate Scholarship from the Government of Canada, a Canadian Institutes of Health Research (CIHR) MD/PhD Studentship, a MD/PhD Studentship from Alberta Innovates-Health Solutions (AI-HS), and a Killam Trust Award. XT received a post-doctoral fellowship from the Canadian Breast Cancer Foundation (CBCF). GV and RTB received studentships from the Women and Children's Health Research Institute (WCHRI) at the University of Alberta, and GV from AI-HS. The work was also supported by grants from the CBCF, CIHR with WCHRI, and Ono Pharmaceuticals Ltd.
- Received Date: 2015-04-11
- Rev Recd Date: 2015-05-12
- Publish Date: 2016-07-28
Abstract: Extracellular lysophosphatidate (LPA) is a potent bioactive lipid that signals through six G-protein-coupled receptors. This signaling is required for embryogenesis, tissue repair and remodeling processes. LPA is produced from circulating lysophosphatidylcholine by autotaxin (ATX), and is degraded outside cells by a family of three enzymes called the lipid phosphate phosphatases (LPPs). In many pathological conditions, particularly in cancers, LPA concentrations are increased due to high ATX expression and low LPP activity. In cancers, LPA signaling drives tumor growth, angiogenesis, metastasis, resistance to chemotherapy and decreased effcacy of radiotherapy. Hence, targeting the ATX-LPA-LPP axis is an attractive strategy for introducing novel adjuvant therapeutic options. In this review, we will summarize current progress in targeting the ATX-LPA-LPP axis with inhibitors of autotaxin activity, LPA receptor antagonists, LPA monoclonal antibodies, and increasing low LPP expression. Some of these agents are already in clinical trials and have applications beyond cancer, including chronic infammatory diseases.
|Citation:||Matthew G.K. Benesch, Xiaoyun Tang, Ganesh Venkatraman, Raie T. Bekele, David N. Brindley. Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo[J]. The Journal of Biomedical Research, 2016, 30(4): 272-284. doi: 10.7555/JBR.30.20150058|