TY - JOUR
T1 - Lysophosphatidic Acid and Autotaxin Stimulate Cell Motility of Neoplastic and Non-neoplastic Cells through LPA
AU - Hama, Kotaro
AU - Aoki, Junken
AU - Fukaya, Masahiro
AU - Kishi, Yasuhiro
AU - Sakai, Teruyuki
AU - Suzuki, Rika
AU - Ohta, Hideo
AU - Yamori, Takao
AU - Watanabe, Masahiko
AU - Chun, Jerold
AU - Arai, Hiroyuki
PY - 2004/4/23
Y1 - 2004/4/23
N2 - Autotaxin (ATX) is a tumor cell motility-stimulating factor originally isolated from melanoma cell supernatant that has been implicated in regulation of invasive and metastatic properties of cancer cells. Recently, we showed that ATX is identical to lysophospholipase D, which converts lysophosphatidylcholine to a potent bioactive phospholipid mediator, lysophosphatidic acid (LPA), raising the possibility that autocrine or paracrine production of LPA by ATX contributes to tumor cell motility. Here we demonstrate that LPA and ATX mediate cell motility-stimulating activity through the LPA receptor, LPA 1. In fibroblasts isolated from lpa1-/- mice, but not from wild-type of lpa2-/-, cell motility stimulated with LPA and ATX was completely absent. In the lpa1 -/- cells, LPA-stimulated lamellipodia formation was markedly diminished with a concomitant decrease in Rac1 activation. LPA stimulated the motility of multiple human cancer cell lines expressing LPA1, and the motility was attenuated by an LPA1-selective antagonist, Ki16425. The present study suggests that ATX and LPA1 represent potential targets for cancer therapy.
AB - Autotaxin (ATX) is a tumor cell motility-stimulating factor originally isolated from melanoma cell supernatant that has been implicated in regulation of invasive and metastatic properties of cancer cells. Recently, we showed that ATX is identical to lysophospholipase D, which converts lysophosphatidylcholine to a potent bioactive phospholipid mediator, lysophosphatidic acid (LPA), raising the possibility that autocrine or paracrine production of LPA by ATX contributes to tumor cell motility. Here we demonstrate that LPA and ATX mediate cell motility-stimulating activity through the LPA receptor, LPA 1. In fibroblasts isolated from lpa1-/- mice, but not from wild-type of lpa2-/-, cell motility stimulated with LPA and ATX was completely absent. In the lpa1 -/- cells, LPA-stimulated lamellipodia formation was markedly diminished with a concomitant decrease in Rac1 activation. LPA stimulated the motility of multiple human cancer cell lines expressing LPA1, and the motility was attenuated by an LPA1-selective antagonist, Ki16425. The present study suggests that ATX and LPA1 represent potential targets for cancer therapy.
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U2 - 10.1074/jbc.M313927200
DO - 10.1074/jbc.M313927200
M3 - Article
C2 - 14744855
AN - SCOPUS:2342437623
VL - 279
SP - 17634
EP - 17639
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 17
ER -