Carba analogs of cyclic phosphatidic acid are selective inhibitors of autotaxin and cancer cell invasion and metastasis

doi:10.1074/jbc.M512486200

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Papers In Press, published online ahead of print June 16, 2006
J. Biol. Chem, 10.1074/jbc.M512486200
Submitted on November 22, 2005
Revised on June 7, 2006
Accepted on June 16, 2006

Carba analogs of cyclic phosphatidic acid are selective inhibitors of autotaxin and cancer cell invasion and metastasis

Daniel L Baker, Yuko Fujiwara, Kathryn R. Pigg, Ryoko Tsukahara, Susumu Kobayashi, Hiromu Murofushi, Ayako Uchiyama, Kimiko Murakami-Murofushi, Eunjin Koh, Russell W. Bandle, Hoe-Sup Byun, Robert Bittman, Dominic Fan, Mandi Murph, Gordon B. Mills, and Gabor Tigyi

Physiology, UTHSC, Memphis, TN 38163

Corresponding Author: gtigyi{at}physio1.utmem.edu

Autotaxin (ATX, nucleotide pyrophosphate/phosphodiesterase-2, NPP2) 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 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.

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