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Carba Analogs of Cyclic Phosphatidic Acid are Selective Inhibitors of Autotaxin and Cancer Cell Invasion and Metastasis
Author(s) -
Fujiwara Yuko,
Baker Daniel L,
Kobayashi Susumu,
MurofushiMurakami Kimiko,
Bittman Robert,
Mills Gordon B,
Tigyi Gabor
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a486-c
Subject(s) - autotaxin , lysophosphatidic acid , phosphatidic acid , cancer cell , cancer research , biology , receptor , autocrine signalling , metastasis , microbiology and biotechnology , cell migration , cell growth , cell , cancer , chemistry , biochemistry , phospholipid , genetics , membrane
Autotaxin (ATX, nucleotide pyrophosphate/phosphodiesterase 2, NPP2) is an autocrine motility factor that was initially isolated from 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). LPA is also known to be an important mediator of cancer cell survival, growth and invasion. Production of LPA is sufficient to explain the effects of ATX on tumor cells. Cyclic phosphatidic acid (cPA) is a naturally occurring, stable 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 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 has remained unresolved. Here we show that 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 . This work was supported by USPHS & UT Cancer Institute Pilot Grant.