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J. Biol. Chem., Vol. 281, Issue 32, 22786-22793, August 11, 2006

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Carba Analogs of Cyclic Phosphatidic Acid Are Selective Inhibitors of Autotaxin and Cancer Cell Invasion and Metastasis^*

From the ^aDepartment of Medicine and the ^bVascular Biology and ^cGenomics and Bioinformatics Centers of Excellence and ^eDepartment of Physiology, The University of Tennessee Health Science Center, Memphis, Tennessee 38163, ^dThe University of Tennessee Cancer Institute, Memphis, Tennessee 38163, ^fDepartment of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Science University of Tokyo, Chiba 278-8510, Japan, ^gDepartment of Biological Science, Faculty of Natural Sciences, Yamaguchi University, Yamaguchi 753-8511, Japan, ^hDepartment of Biology, Faculty of Science, Ochanomizu University, Tokyo 112-8610, Japan, ⁱLaboratory of Pathology, NCI, National Institutes of Health, Bethesda, Maryland 20892, ^jDepartment of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, New York 11367, and ^kDepartments of Cancer Biology and ^lMolecular Therapeutics, M.D. Anderson Cancer Center, The University of Texas, Houston, Texas 77030

Autotaxin (ATX, nucleotide pyrophosphate/phosphodiesterase-2) is an autocrine motility factor initially characterized from A2058 melanoma cell-conditioned medium. ATX is known to contribute to cancer cell survival, growth, and invasion. Recently ATX was shown to be responsible for the lysophospholipase D activity that generates lysophosphatidic acid (LPA). Production of LPA is sufficient to explain the effects of ATX on tumor cells. Cyclic phosphatidic acid (cPA) is a naturally occurring analog of LPA in which the sn-2 hydroxy group forms a 5-membered ring with the sn-3 phosphate. Cellular responses to cPA generally oppose those of LPA despite activation of apparently overlapping receptor populations, suggesting that cPA also activates cellular targets distinct from LPA receptors. cPA has previously been shown to inhibit tumor cell invasion in vitro and cancer cell metastasis in vivo. However, the mechanism governing this effect remains unresolved. Here we show that 3-carba analogs of cPA lack significant agonist activity at LPA receptors yet are potent inhibitors of ATX activity, LPA production, and A2058 melanoma cell invasion in vitro and B16F10 melanoma cell metastasis in vivo.

Received for publication, November 22, 2005 , and in revised form, June 7, 2006.

^* This research was supported in part by American Heart Association Award 0535195N and a University of Tennessee Cancer Institute Pilot Grant (to D. L. B.), the Intramural Research Program of the NCI, National Institutes of Health, Center for Cancer Research (to R. W. B.), United States Public Health Service Grants PO1 CA64602 and DAMD 17-02-1-0694 (to G. B. M.), and CA92160, HL61469, and HL79004 (to G. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ These authors contributed equally.

² To whom correspondence should be addressed: Dept. of Physiology, The University of Tennessee Health Science Center, 894 Union Ave., Memphis, TN 38163. Tel.: 901-448-4793; Fax: 901-448-7126, E-mail: gtigyi{at}physio1.utmem.edu.

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