Carba analogs of cyclic phosphatidic acid are selective inhibitors of autotaxin and cancer cell invasion and metastasis
Carba analogs of cyclic phosphatidic acid are selective inhibitors of autotaxin and cancer cell invasion and metastasis
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DOI：
10.1074/jbc.m512486200
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发表时间：
2006-08-11
影响因子：
4.8
通讯作者：
Tigyi, Gabor
中科院分区：
文献类型：
--
作者：
Baker, Daniel L.;Fujiwara, Yuko;Tigyi, Gabor
自分泌运动因子（ATX，核苷酸焦磷酸/磷酸二酯酶-2）是一种自分泌运动因子，最初是从 A2058 黑色素瘤细胞条件培养基中表征的。众所周知，ATX 有助于癌细胞的存活、生长和侵袭。最近，ATX 被证明负责产生溶血磷脂酸 (LPA) 的溶血磷脂酶 D 活性。 LPA的产生足以解释ATX对肿瘤细胞的影响。环状磷脂酸 (cPA) 是 LPA 的天然类似物，其中 sn-2 羟基与 sn-3 磷酸酯形成 5 元环。尽管激活了明显重叠的受体群，但细胞对 cPA 的反应通常与 LPA 的反应相反，这表明 cPA 也激活与 LPA 受体不同的细胞靶标。 cPA 先前已被证明可抑制体外肿瘤细胞侵袭和体内癌细胞转移。然而，控制这种效应的机制仍未解决。在这里，我们发现 cPA 的 3-carba 类似物对 LPA 受体缺乏显着的激动剂活性，但却是 ATX 活性、LPA 产生、体外 A2058 黑色素瘤细胞侵袭和体内 B16F10 黑色素瘤细胞转移的有效抑制剂。
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.