Phospholipase D inhibitors reduce human prostate cancer cell proliferation and colony formation.
Phospholipase D inhibitors reduce human prostate cancer cell proliferation and colony formation.
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磷脂酶D抑制剂减少了人类前列腺癌细胞的增殖和菌落形成。
DOI：
10.1038/bjc.2017.391
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发表时间：
2018-01
影响因子：
8.8
通讯作者：
Rumsby MG
中科院分区：
文献类型：
--
作者：
Noble AR;Maitland NJ;Berney DM;Rumsby MG
磷脂酶D_1和D_2(PLD_1/2)水解膜甘油磷脂生成磷脂酸，磷脂酸是一种信号脂质，通过影响mTOR和PKB/Akt来调节细胞生长和肿瘤进展。PLD在乳腺癌、结直肠癌、胃癌、肾癌和甲状腺癌中的表达和/或活性增加，但其在前列腺癌(PCa)中的作用尚不清楚。前列腺癌是西方世界男性的主要癌症。用免疫印迹法检测培养的PNT2C2、PNT1A、P4E6、LNCaP、PC3、PC3M、VCaP、22Rv1细胞和患者来源的PCa细胞中PLD1蛋白的表达。用免疫组织化学方法检测了正常前列腺、良性前列腺增生症(BPH)、去势耐药前列腺癌(CRPC)组织切片和前列腺癌组织芯片(TMA)中PLD1蛋白的定位。用Amplex Red法检测PCa组织中PLD活性。用MTS法和集落形成实验检测PLD抑制剂对PCa细胞活力的影响。腔内前列腺细胞系(LNCaP、VCaP、22Rv1)的PLD1蛋白表达水平低于基础系(PC3、PC3M)。PLD1蛋白在BPH活检组织中的表达高于正常组织和PCa组织。在正常组织和BPH组织中，PLD1主要表达于基底细胞以及部分间质细胞，而不是腔细胞。在前列腺癌组织中，腔上皮细胞表达PLD1。在PCa TMA中，Gleason 6和Gleason 7组织切片DAB染色的平均过氧化物酶强度显著高于Gleason 9组织切片。在CRPC组织中，PLD1在间质间质、偶见腺体的管腔细胞和大量共同表达嗜铬粒蛋白A和神经元特异性烯醇化酶的细胞中显著表达。正常组织和前列腺癌组织中PLD活性水平相似。与两种PLD1/PLD2双重抑制剂相比，一种特异的PLD1抑制剂显著降低了前列腺癌细胞系和患者来源的PCa细胞的存活率。短期暴露于相同特异性PLD1抑制剂的PCa细胞显著减少集落形成。一种新的PLD1特异性抑制剂，在小鼠中具有良好的耐受性，可以降低PCa细胞的存活率，因此有可能成为一种新型的治疗药物来减缓前列腺癌的进展。PLD1的表达增加可能与BPH的增生特征和去势抵抗的PCa的进展有关，在那里，不断扩大的神经内分泌样细胞群表达PLD1。
Phospholipases D1 and D2 (PLD1/2) hydrolyse cell membrane glycerophospholipids to generate phosphatidic acid, a signalling lipid, which regulates cell growth and cancer progression through effects on mTOR and PKB/Akt. PLD expression and/or activity is raised in breast, colorectal, gastric, kidney and thyroid carcinomas but its role in prostate cancer (PCa), the major cancer of men in the western world, is unclear. PLD1 protein expression in cultured PNT2C2, PNT1A, P4E6, LNCaP, PC3, PC3M, VCaP, 22RV1 cell lines and patient-derived PCa cells was analysed by western blotting. PLD1 protein localisation in normal, benign prostatic hyperplasia (BPH), and castrate-resistant prostate cancer (CRPC) tissue sections and in a PCa tissue microarray (TMA) was examined by immunohistochemistry. PLD activity in PCa tissue was assayed using an Amplex Red method. The effect of PLD inhibitors on PCa cell viability was measured using MTS and colony forming assays. PLD1 protein expression was low in the luminal prostate cell lines (LNCaP, VCaP, 22RV1) compared with basal lines (PC3 and PC3M). PLD1 protein expression was elevated in BPH biopsy tissue relative to normal and PCa samples. In normal and BPH tissue, PLD1 was predominantly detected in basal cells as well in some stromal cells, rather than in luminal cells. In PCa tissue, luminal cells expressed PLD1. In a PCa TMA, the mean peroxidase intensity per DAB-stained Gleason 6 and 7 tissue section was significantly higher than in sections graded Gleason 9. In CRPC tissue, PLD1 was expressed prominently in the stromal compartment, in luminal cells in occasional glands and in an expanding population of cells that co-expressed chromogranin A and neurone-specific enolase. Levels of PLD activity in normal and PCa tissue samples were similar. A specific PLD1 inhibitor markedly reduced the survival of both prostate cell lines and patient-derived PCa cells compared with two dual PLD1/PLD2 inhibitors. Short-term exposure of PCa cells to the same specific PLD1 inhibitor significantly reduced colony formation. A new specific inhibitor of PLD1, which is well tolerated in mice, reduces PCa cell survival and thus has potential as a novel therapeutic agent to reduce prostate cancer progression. Increased PLD1 expression may contribute to the hyperplasia characteristic of BPH and in the progression of castrate-resistant PCa, where an expanding population of neuroendocrine-like cells express PLD1.
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影响因子：
5.2
作者：
Hägglöf C;Bergh A
通讯作者：
Bergh A
影响因子：
8.8
作者：
Frame, F. M.;Pellacani, D.;Collins, A. T.;Simms, M. S.;Mann, V. M.;Jones, G. D. D.;Meuth, M.;Bristow, R. G.;Maitland, N. J.
通讯作者：
Maitland, N. J.
影响因子：
5.3
作者：
Henkels, Karen M.;Peng, Hong-Juan;Gomez-Cambronero, Julian
通讯作者：
Gomez-Cambronero, Julian
影响因子：
3.3
作者：
Freyberg, Z;Sweeney, D;Shields, D
通讯作者：
Shields, D
DOI：
10.1007/978-1-4939-3724-0_12
发表时间：
2016-01-01
期刊：
NUCLEAR RECEPTOR SUPERFAMILY: METHODS AND PROTOCOLS, 2ND EDITION
影响因子：
--
作者：
Frame, Fiona M.;Pellacani, Davide;Maitland, Norman J.
通讯作者：
Maitland, Norman J.