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Autotaxin promotes cancer invasion via the lysophosphatidic acid receptor 4: participation of the cyclic AMP/EPAC/Rac1 signaling pathway in invadopodia formation.

Abstract
The ability of cancer cells to invade and metastasize is the major cause of death in cancer patients. Autotaxin (ATX) is a secreted lysophospholipase whose level of expression within tumors correlates strongly with their aggressiveness and invasiveness. ATX is the major enzyme involved in the production of lysophosphatidic acid (LPA), a phospholipid that is known to act mostly through its three first characterized receptors (LPA(1), LPA(2), and LPA(3)). Tumor cell invasion across tissue boundaries and metastasis are dependent on the capacity of invasive cancer cells to breach the basement membrane. This process can be initiated by the formation of the actin-rich cell protrusions, invadopodia. In this study, we show that ATX is implicated in the formation of invadopodia in various cancer cells types and this effect is dependent on the production of LPA. We further provide evidence that LPA(4) signaling in fibrosarcoma cells regulates invadopodia formation downstream of ATX, a process mediated through the activation of EPAC by cyclic AMP and subsequent Rac1 activation. Results using LPA(4) shRNA support the requirement of the LPA(4) receptor for cell invasion and in vivo metastasis formation. This work presents evidence that blocking the LPA receptor, LPA(4), in fibrosarcoma cells could provide an additional tool to improve the efficacy of treatment of metastasis in patients. Because LPA receptors and ATX are currently being targeted in preclinical trials, the current findings should stimulate future studies to evaluate the expression pattern and clinical outcome of LPA(4), together with other LPA receptors, in various cancer patients.
AuthorsKelly Harper, Dominique Arsenault, Stephanie Boulay-Jean, Annie Lauzier, Fabrice Lucien, Claire M Dubois
JournalCancer research (Cancer Res) Vol. 70 Issue 11 Pg. 4634-43 (Jun 01 2010) ISSN: 1538-7445 [Electronic] United States
PMID20484039 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright 2010 AACR.
Chemical References
  • Guanine Nucleotide Exchange Factors
  • LPAR4 protein, human
  • Multienzyme Complexes
  • RAC1 protein, human
  • RAPGEF3 protein, human
  • Receptors, Purinergic P2
  • Cyclic AMP
  • Phosphoric Diester Hydrolases
  • Phosphodiesterase I
  • alkylglycerophosphoethanolamine phosphodiesterase
  • Pyrophosphatases
  • rac1 GTP-Binding Protein
Topics
  • Animals
  • Caco-2 Cells
  • Cell Line, Tumor
  • Cyclic AMP (biosynthesis, metabolism)
  • Female
  • Guanine Nucleotide Exchange Factors (metabolism)
  • Humans
  • Mice
  • Mice, Nude
  • Multienzyme Complexes (metabolism)
  • Neoplasm Invasiveness
  • Neoplasms (enzymology, metabolism, pathology)
  • Phosphodiesterase I (metabolism)
  • Phosphoric Diester Hydrolases
  • Pyrophosphatases (metabolism)
  • Receptors, Purinergic P2 (metabolism)
  • Signal Transduction
  • rac1 GTP-Binding Protein (metabolism)

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