TY - JOUR
T1 - Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production
AU - Aoki, Junken
AU - Kishi, Yasuhiro
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2003
Y1 - 2003
N2 - Autotaxin (ATX) is a tumor cell motility-stimulating factor, originally isolated from melanoma cell supernatants. ATX had been proposed to mediate its effects through 5′-nucleotide pyrophosphatase and phosphodiesterase activities. However, the ATX substrate mediating the increase in cellular motility remains to he identified. Here, we demonstrated that lysophospholipase D (lysoPLD) purified from fetal bovine serum, which catalyzes the production of the bioactive phospholipid mediator, lysophosphatidic acid (LPA), from lysophosphatidylcholine(LPC), is identical to ATX. The Km value of ATX for LPC was 25-fold lower than that for the synthetic nucleoside substrate, p-nitrophenyl-tri-monophosphate. LPA mediates multiple biological functions including cytoskeletal reorganization, chemotaxis and cell growth through activation of specific G-protein-coupled receptors. Recombinant ATX, particularly in the presence of LPC, dramatically increased chemotaxis and proliferation of multiple different cell lines. Moreover, we demonstrate that several cancer cell lines release significant amounts of LPC, a substrate for ATX, into the culture medium. The demonstration that ATX and lysoPLD are identical suggests that autocrine or paracrine production of LPA contributes to tumor cell motility, survival and proliferation. It also provides potential novel targets for therapy of pathophysiological states, including cancer.
AB - Autotaxin (ATX) is a tumor cell motility-stimulating factor, originally isolated from melanoma cell supernatants. ATX had been proposed to mediate its effects through 5′-nucleotide pyrophosphatase and phosphodiesterase activities. However, the ATX substrate mediating the increase in cellular motility remains to he identified. Here, we demonstrated that lysophospholipase D (lysoPLD) purified from fetal bovine serum, which catalyzes the production of the bioactive phospholipid mediator, lysophosphatidic acid (LPA), from lysophosphatidylcholine(LPC), is identical to ATX. The Km value of ATX for LPC was 25-fold lower than that for the synthetic nucleoside substrate, p-nitrophenyl-tri-monophosphate. LPA mediates multiple biological functions including cytoskeletal reorganization, chemotaxis and cell growth through activation of specific G-protein-coupled receptors. Recombinant ATX, particularly in the presence of LPC, dramatically increased chemotaxis and proliferation of multiple different cell lines. Moreover, we demonstrate that several cancer cell lines release significant amounts of LPC, a substrate for ATX, into the culture medium. The demonstration that ATX and lysoPLD are identical suggests that autocrine or paracrine production of LPA contributes to tumor cell motility, survival and proliferation. It also provides potential novel targets for therapy of pathophysiological states, including cancer.
KW - autotaxin
KW - cancer
KW - lysoPLD
KW - lysophosphatidic acid
KW - metastasis/invasion
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U2 - 10.2745/dds.18.361
DO - 10.2745/dds.18.361
M3 - Article
AN - SCOPUS:85024462002
VL - 18
SP - 361
EP - 366
JO - Drug Delivery System
JF - Drug Delivery System
SN - 0913-5006
IS - 4
ER -