Abstract
Autotaxin (ATX) promotes cancer cell metastasis through the production of lysophosphatidic acid (LPA). ATX binds to αvβ3 integrins controlling metastasis of breast cancer cells. We screened a series of cancer cell lines derived from diverse human and mouse solid tumors for the capacity of binding to ATX and found only a modest correlation with their level of αvβ3 integrin expression. These results strongly suggested the existence of another cell surface ATX-interacting factor. Indeed, ATXα has been shown to bind heparan-sulfate chains because of its unique polybasic insertion sequence, although the biological significance is unknown. We demonstrated here, that among all cell surface heparan-sulfate proteoglycans, syndecan-4 (SDC4) was essential for cancer cell interaction with ATXβ but was restrained by heparan-sulfate chains. In addition, exogenous ATXβ-induced MG63 osteosarcoma cell proliferation required physical interaction of ATXβ with the cell surface via an SDC4-dependent mechanism. In a preclininal mouse model, targeting SDC4 on 4T1 mouse breast cancer cells inhibited early bone metastasis formation. Furthermore, SDC4-prometastatic activity was totally abolished in absence of ATX expression. In conclusion our results determined that ATX and SDC4 are engaged in a reciprocal collaboration for cancer cell metastasis providing the rational for the development of novel anti-metastasis therapies.
Highlights
Autotaxin (ATX) is a unique member of the nucleotide pyrophosphatases phosphodiesterase family because of its characteristic lysophospholipase D activity that is responsible for the synthesis of lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC) and other lysophospholipid precursors [1]
We identified HS proteoglycan syndecan-4 (SDC4) as a new molecule that controls ATXβ interaction with cancer cell surface through a domain located in SDC4 core protein
These results support the existence of complementary mechanisms that in addition to αvβ3 integrins are involved in ATXβ binding with the cell surface
Summary
Autotaxin (ATX) is a unique member of the nucleotide pyrophosphatases phosphodiesterase family because of its characteristic lysophospholipase D (lysoPLD) activity that is responsible for the synthesis of lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC) and other lysophospholipid precursors [1]. The recent resolution of ATX crystal structure led to the identification of amino acids E109 and H117 located in the somatomedin B-like domain 2 that are involved in ATX binding to β3 integrins (αvβ, αIIbβ3) [16, 17]. This binding has a functional impact on ATX as it increases lysoPLD activity [17], promotes cancer cell motility [18] and metastasis [19]. These studies supported the concept for a novel biological way of action of ATX involving the binding to β3 integrins that might localize ATX activity to the cell surface, providing a favorable environment for LPA production and action in the close vicinity of its cell surface receptors
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