Purinergic regulation of angiogenesis by human breast carcinoma-secreted nucleoside diphosphate kinase.
Purinergic regulation of angiogenesis by human breast carcinoma-secreted nucleoside diphosphate kinase.
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DOI：
10.1038/sj.bjc.6604019
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发表时间：
2007-11-19
影响因子：
8.8
通讯作者：
Buxton, I L O
中科院分区：
文献类型：
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作者：
Rumjahn, S M;Javed, M A;Wong, N;Law, W E;Buxton, I L O
MDA-MB-435S 人乳腺癌细胞 (435S) 分泌核苷二磷酸激酶 (NDPK)，支持转移，并受到表没食子儿茶素没食子酸酯 (EGCG) 和鞣花酸 (EA) 的抑制。我们假设 435S 细胞分泌的 NDPK-B 通过局部调节 ATP 水平以激活内皮细胞 (EC) P2Y 受体介导的血管生成来支持肿瘤形成。表没食子儿茶素没食子酸酯 (IC50=8–10μM) 和 EA (IC50=2–3μM) 抑制 435S 细胞生长，但对人 CD31+ EC 生长影响较小。表没食子儿茶素没食子酸酯 (IC50=11μM) 和 EA (IC50=1μM) 也能阻止 Matrigel™ 上的 CD31+ EC 小管形成。 435S细胞条件培养基以细胞数量、时间和核苷酸依赖性方式诱导肾小管发生。鞣花酸（1μM），但不是等摩尔的 EGCG，减少了细胞数量依赖性血管生成。 NDPK 生成的核苷酸 (100μM ATP) 或 10μM 2-甲硫基-ATP (2MS-ATP) 激活 P2Y1 受体，促进胶原上的小管形成，并被 P2Y1 拮抗剂 MRS2179 (10μM) 阻断。生理量的纯化以及435S细胞分泌的NDPK也促进血管生成，该血管生成因NDPK耗尽或10μM MRS2179而减弱，表明P2Y1受体介导的途径。这些结果支持分泌型 NDPK 通过 P2Y 受体信号传导介导血管生成的观点，并表明新型 NDPK 抑制剂可能可用作治疗药物。
MDA-MB-435S human breast cancer cells (435S) secrete nucleoside diphosphate kinase (NDPK) that supports metastases and is inhibited by epigallocatechin gallate (EGCG) and ellagic acid (EA). We hypothesise that 435S cell-secreted NDPK-B supports tumour formation by modulating ATP levels locally to activate endothelial cell (EC) P2Y receptor-mediated angiogenesis. Epigallocatechin gallate (IC50=8–10 μM) and EA (IC50=2–3 μM) suppressed 435S cell growth, but had less effect on human CD31+ EC growth. Epigallocatechin gallate (IC50=11 μM) and EA (IC50=1 μM) also prevented CD31+ EC tubulogenesis on Matrigel™. 435S cell-conditioned media induced tubulogenesis in a cell number, time, and nucleotide-dependent manner. Ellagic acid (1 μM), but not equimolar EGCG, reduced cell number-dependent angiogenesis. P2Y1 receptor activation by NDPK-generated nucleotide (100 μM ATP) or by 10 μM 2-methyl-thio-ATP (2MS-ATP) promoted tubulogenesis on collagen and was blocked by the P2Y1 antagonist MRS2179 (10 μM). Physiological amounts of purified as well as 435S cell-secreted NDPK also promoted angiogenesis that was attenuated by NDPK depletion or 10 μM MRS2179, indicating a P2Y1 receptor-mediated pathway. These results support the notion that secreted NDPK mediates angiogenesis via P2Y receptor signalling and suggests that novel inhibitors of NDPK may be useful as therapeutics.