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Alkoxymethylenephosphonate Analogues of (Lyso)phosphatidic Acid Stimulate Signaling Networks Coupled to the LPA 2 Receptor
Author(s) -
Gajewiak Joanna,
Tsukahara Ryoko,
Tsukahara Tamotsu,
Yu Shuanxing,
Lu Yiling,
Murph Mandi,
Mills Gordon B.,
Tigyi Gabor,
Prestwich Glenn D.
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700111
Subject(s) - lysophosphatidic acid , phosphatidic acid , agonist , receptor , signal transduction , chemistry , g protein coupled receptor , protein kinase b , microbiology and biotechnology , phosphorylation , biology , biochemistry , phospholipid , membrane
An efficient stereocontrolled synthesis afforded alkoxymethylenephosphonate (MP) analogues of lysophosphatidic acid (LPA) and phosphatidic acid (PA). The pharmacological properties of MP‐LPA and MP‐PA analogues were characterized for LPA receptor subtype‐specific agonist and antagonist activity using Ca 2+ ‐mobilization assays in RH7777 cells expressing the individual LPA 1 –LPA 3 receptors and CHO cells expressing LPA 4 . In addition, activation of a PPARγ reporter gene construct expressed in CV‐1 cells was assessed. These metabolically stabilized LPA analogues exhibited an unexpected pattern of partial agonist/antagonist activity for the LPA G‐protein‐coupled receptor family and the intracellular LPA receptor PPARγ. Analogues were compared with 18:1 LPA for activation of downstream signaling in HT‐29 colon cancer cells, which exclusively express LPA 2 , and both SKOV3 and OVCAR3 ovarian cancer cells, which express LPA 1 , LPA 2 , and LPA 3 . Unexpectedly, reverse phase protein arrays showed that four MP‐LPA and MP‐PA analogues selectively activated downstream signaling in HT‐29 cells with greater potency than LPA. In particular, the oleoyl MP‐LPA analogue strongly promoted phosphorylation and activation of AKT, MEK, and pS6 in HT‐29 cells in a concentration‐dependent manner. In contrast, the four MP‐LPA and MP‐PA analogues were equipotent with LPA for pathway activation in the SKOV3 and OVCAR3 cells. Taken together, these results suggest that the MP analogues may selectively activate signaling via the LPA 2 receptor subtype, while simultaneously suppressing signaling through the LPA 1 and LPA 3 subtypes.