Cytosolic phospholipase A2-alpha: a potential therapeutic target for prostate cancer.
Cytosolic phospholipase A2-alpha: a potential therapeutic target for prostate cancer.
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胞质磷脂酶A2-Alpha：前列腺癌的潜在治疗靶标。
DOI：
10.1158/1078-0432.ccr-08-0566
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发表时间：
2008-12-15
期刊：
影响因子：
--
通讯作者：
Dong Q
中科院分区：
文献类型：
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作者：
Patel MI;Singh J;Niknami M;Kurek C;Yao M;Lu S;Maclean F;King NJ;Gelb MH;Scott KF;Russell PJ;Boulas J;Dong Q
胞浆磷脂酶A2-α（cPLA 2-α）提供细胞内花生四烯酸以供应环氧合酶和脂氧合酶途径。本研究旨在探讨cPLA 2-α在前列腺癌（PC）细胞系和组织中的表达和活化，以及cPLA 2-α靶向治疗的体内外效应。用RT-PCR、Western blot和免疫细胞化学方法检测PC细胞中cPLA 2-α的表达。用cPLA 2-α siRNA或抑制剂（Wyeth-1）抑制细胞生长、凋亡和cPLA 2-α活性。还向PC异种移植小鼠模型施用cPLA 2-α抑制剂或媒介物。最后用免疫组化法检测正常人、雄激素敏感者和雄激素不敏感者前列腺癌组织中磷酸化cPLA 2-α的表达。cPLA 2-α存在于所有PC细胞系中，但在雄激素不敏感细胞中增加。siRNA或Wyeth-1抑制导致PC细胞数量显著减少，这是增殖减少以及凋亡增加的结果，这也与cPLA 2-α活性降低相关。细胞周期蛋白D1的表达和Akt的磷酸化也被观察到减少。Wyeth-1抑制PC 3异种移植物生长约33%，并再次降低细胞周期蛋白D1。人前列腺组织的免疫组织化学显示，当达到激素难治性时，磷酸化cPLA 2-α增加。cPLA 2-α表达和活化在雄激素不敏感的癌细胞系和组织中增加。cPLA 2-α的抑制导致细胞和异种移植肿瘤生长抑制，并作为激素难治性PC的潜在有效疗法。
Cytosolic Phospholipase A2-α (cPLA2-α) provides intracellular arachidonic acid to supply both cyclooxygenase and lipoxygenase pathways. We aim to determine the expression and activation of cPLA2-α in prostate cancer (PC) cell line and tissue and the effect of targeting cPLA2-α in-vitro and in-vivo. The expression of cPLA2-α was determined in PC cells by RT-PCR, Western blot and immunocytochemistry. Growth inhibition, apoptosis and cPLA2-α activity were determined after inhibition with cPLA2-α siRNA or inhibitor (Wyeth-1). cPLA2-α inhibitor or vehicle was also administered to PC xenograft mouse models. Finally the expression of phospho-cPLA2-α was determined by immunohistochemistry in human normal, androgen sensitive and insensitive PC specimens. cPLA2-α is present in all PC cells lines, but increased in androgen insensitive cells. Inhibition with siRNA or Wyeth-1 results in significant reductions in PC cell numbers, as a result of reduced proliferation as well as increased apoptosis and this was also associated with a reduction in cPLA2-α activity. Expression of cyclin D1 and phosphorylation of Akt were also observed to decrease. Wyeth-1 inhibited PC3 xenograft growth by approximately 33% and again, also reduced cyclin D1. Immunohistochemistry of human prostate tissue revealed that phospho-cPLA2-α is increased when hormone refractory is reached. cPLA2-α expression and activation is increased in the androgen insensitive cancer cell line and tissue. Inhibition of cPLA2-α results in cells and xenograft tumor growth inhibition and serves as a potentially effective therapy for hormone refractory PC.