Carba analogs of cyclic phosphatidic acid are selective inhibitors of autotaxin and cancer cell invasion and metastasis.
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.
Baker
Daniel L
DL
Department of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Fujiwara
Yuko
Y
Pigg
Kathryn R
KR
Tsukahara
Ryoko
R
Kobayashi
Susumu
S
Murofushi
Hiromu
H
Uchiyama
Ayako
A
Murakami-Murofushi
Kimiko
K
Koh
Eunjin
E
Bandle
Russell W
RW
Byun
Hoe-Sup
HS
Bittman
Robert
R
Fan
Dominic
D
Murph
Mandi
M
Mills
Gordon B
GB
Tigyi
Gabor
G
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D006801:Humans; D050356:Lipid Metabolism; D008246:Lysophospholipids / Q000494:pharmacology; D008545:Melanoma / Q000378:metabolism; D009097:Multienzyme Complexes / Q000737:chemistry*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010712:Phosphatidic Acids / Q000737:chemistry*; D043264:Phosphodiesterase I / Q000737:chemistry*; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D000099189:Lysophospholipase D
D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D010712:Phosphatidic Acids; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D011994:Recombinant Proteins; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid