Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume 1831, Issue 1, Pages 74-85Publisher
ELSEVIER
DOI: 10.1016/j.bbalip.2012.08.015
Keywords
Ceramide; Lipid phosphate phosphatase; Metastasis; Phospholipase D; Sphingosine kinase; LPA(2)
Funding
- Canadian Institutes of Health Research
- Alberta Cancer Foundation
- Canadian Breast Cancer Foundation
- National Cancer Institute
- National Institute of Allergy Medical Countermeasures Radiological and Nuclear Threats Program [CA92160, AI80405]
- Harriet Van Vleet Endowment for Basic Oncology Research
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High expression of autotaxin in cancers is often associated with increased tumor progression, angiogenesis and metastasis. This is explained mainly since autotaxin produces the lipid growth factor, lysophosphatidate (LPA), which stimulates cell division, survival and migration. It has recently become evident that these signaling effects of LPA also produce resistance to chemotherapy and radiation-induced cell death. This results especially from the stimulation of LPA(2) receptors, which depletes the cell of Siva-1, a pro-apoptotic signaling protein and stimulates prosurvival kinase pathways through a mechanism mediated via TRIP-6. LPA signaling also increases the formation of sphingosine 1-phosphate, a pro-survival lipid. At the same time, LPA decreases the accumulation of ceramides, which are used in radiation therapy and by many chemotherapeutic agents to stimulate apoptosis. The signaling actions of extracellular LPA are terminated by its dephosphorylation by a family of lipid phosphate phosphatases (LPP) that act as ecto-enzymes. In addition, lipid phosphate phoshatase-1 attenuates signaling downstream of the activation of both LPA receptors and receptor tyrosine kinases. This makes many cancer cells hypersensitive to the action of various growth factors since they often express low LPP1/3 activity. Increasing our understanding of the complicated signaling pathways that are used by LPA to stimulate cell survival should identify new therapeutic targets that can be exploited to increase the efficacy of chemo- and radio-therapy. This article is part of a Special Issue entitled Advances in Lysophospholipid Research. (C) 2012 Elsevier B.V. All rights reserved.
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