Constitutive and lysophosphatidic acid (LPA)-induced LPA production: role of phospholipase D and phospholipase A2.
Constitutive and lysophosphatidic acid (LPA)-induced LPA production: role of phospholipase D and phospholipase A2.
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发表时间：
2000-06
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通讯作者：
A. Eder;T. Sasagawa;T. Sasagawa;M. Mao;J. Aoki;G. Mills
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作者：
A. Eder;T. Sasagawa;T. Sasagawa;M. Mao;J. Aoki;G. Mills
来自卵巢癌患者的腹水和血浆，而不是来自非妇科肿瘤患者的腹水和血浆，含有高水平的生物活性磷脂溶血磷脂酸（LPA）。我们发现，卵巢癌细胞组成性产生的LPA的增加量相比，正常卵巢上皮细胞，卵巢上皮癌的前体，或乳腺癌细胞。此外，LPA而不是其他生长因子增加OVCAR-3卵巢癌细胞系而不是正常卵巢上皮或乳腺癌细胞系的LPA产生。我们发现，磷脂酶D的活性有助于卵巢癌细胞的组成和LPA诱导的LPA生产。卵巢癌细胞的组成性和LPA诱导的LPA合成相对于特定磷脂酶A2（PLA 2）亚组的要求受到差异调节。IB组（胰腺）分泌型PLA 2在组成型和LPA诱导的LPA形成中起关键作用，而IIA组（滑膜）分泌型PLA 2仅有助于LPA诱导的LPA产生。钙依赖性和/或非依赖性胞质PLA 2是组成性LPA合成所需的，但在LPA诱导的LPA形成中不起作用。LPA增加卵巢癌细胞的增殖，降低对卵巢癌中最常用药物顺铂的敏感性，减少细胞凋亡和失巢凋亡，增加蛋白酶产生，并增加新血管形成介质的产生。因此，了解卵巢癌患者LPA产生的来源和调节可以确定新的治疗靶点。
Ascitic fluid and plasma from ovarian cancer patients, but not from patients with nongynecological tumors, contain elevated levels of the bioactive phospholipid lysophosphatidic acid (LPA). We show that ovarian cancer cells constitutively produce increased amounts of LPA as compared with normal ovarian epithelium, the precursor of ovarian epithelial cancer, or breast cancer cells. In addition, LPA, but not other growth factors, increases LPA production by the OVCAR-3 ovarian cancer cell line but not by normal ovarian epithelium or breast cancer cell lines. We show that phospholipase D activity contributes to both constitutive and LPA-induced LPA production by ovarian cancer cells. Constitutive and LPA-induced LPA synthesis by ovarian cancer cells is differentially regulated with respect to the requirement of specific phospholipase A2 (PLA2) subgroups. Group IB (pancreatic) secretory PLA2 plays a critical role in both constitutive and LPA-induced LPA formation, whereas group IIA (synovial) secretory PLA2 contributes to LPA-induced LPA production only. Calcium-dependent and/or -independent cytosolic PLA2s are required for constitutive LPA synthesis but do not play a role in LPA-induced LPA formation. LPA increases the proliferation of ovarian cancer cells, decreases sensitivity to cisplatin, the most commonly used drug in ovarian cancer, decreases apoptosis and anoikis, increases protease production, and increases production of neovascularization mediators. Thus, an understanding of the source and regulation of LPA production in ovarian cancer patients could identify novel targets for therapy.