Neuropeptide Y and its Y2 receptor: potential targets in neuroblastoma therapy.
Neuropeptide Y and its Y2 receptor: potential targets in neuroblastoma therapy.
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DOI：
10.1038/onc.2010.301
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发表时间：
2010-10-14
期刊：
影响因子：
8
通讯作者：
Kitlinska, J.
中科院分区：
文献类型：
--
作者：
Lu, C.;Everhart, L.;Tilan, J.;Kuo, L.;Sun, C-C J.;Munivenkatappa, R. B.;Jonsson-Rylander, A.-C.;Sun, J.;Kuan-Celarier, A.;Li, L.;Abe, K.;Zukowska, Z.;Toretsky, J. A.;Kitlinska, J.
神经母细胞瘤是由交感神经前体细胞发展而来的儿科肿瘤，表达神经元蛋白，如神经肽Y（NPY）。NPY是通过多种受体（Y1-Y 5 R）起作用的交感神经递质。NPY和Y2 Rs通常在神经母细胞瘤细胞系和组织中表达。神经母细胞瘤分泌的肽刺激肿瘤细胞增殖和血管生成。由于这两个过程是Y2 R介导的，本研究的目的是评估Y2 R作为神经母细胞瘤的潜在治疗靶点。在体外，Y2 R拮抗剂（BIIE 0246）阻止了内源性NPY诱导的p44/42 MAPK激活，从而导致Bim介导的细胞增殖和凋亡的诱导。用NPY siRNA和Y2 R siRNA实现了类似的生长抑制作用。在体内，Y2 R拮抗剂显著抑制SK-N-BE（2）和SK-N-AS异种移植物的生长，这与p44/42 MAPK活化减少以及增殖减少（Ki 67）和凋亡增加（TUNEL）有关。Y2 R拮抗剂也具有抗血管生成作用。在体外，它减少了神经母细胞瘤条件培养基诱导的内皮细胞增殖。因此，Y2 R拮抗剂处理的异种移植物具有减少的血管形成和高度的局灶性纤维化。在人神经母细胞瘤组织中，在肿瘤细胞和内皮细胞中观察到Y2 R的表达，而NPY主要在神经母细胞瘤细胞中表达。总之，Y2 R是影响癌细胞和肿瘤血管的神经母细胞瘤治疗的有前途的新靶点。
Neuroblastomas are pediatric tumors which develop from sympathetic precursors and express neuronal proteins, such as neuropeptide Y (NPY). NPY is a sympathetic neurotransmitter acting via multiple receptors (Y1-Y5R). Both NPY and Y2Rs are commonly expressed in neuroblastoma cell lines and tissues. The peptide secreted from neuroblastomas stimulates tumor cell proliferation and angiogenesis. Since both processes are Y2R-mediated, the goal of this study was to assess Y2R as a potential therapeutic target for neuroblastoma. In vitro, Y2R antagonist (BIIE0246) prevented activation of p44/42 MAPK induced by endogenous NPY, which resulted in decreased proliferation and induction of Bim-mediated apoptosis. Similar growth-inhibitory effects were achieved with NPY siRNA and Y2R siRNA. In vivo, Y2R antagonist significantly inhibited growth of SK-N-BE(2) and SK-N-AS xenografts, which was associated with decreased activation of p44/42 MAPK, as well as reduced proliferation (Ki67) and increased apoptosis (TUNEL). The Y2R antagonist also exerted an anti-angiogenic effect. In vitro, it reduced the proliferation of endothelial cells induced by neuroblastoma-conditioned media. Consequently, the Y2R antagonist-treated xenografts had decreased vascularization and a high degree of focal fibrosis. In human neuroblastoma tissues, the expression of Y2R was observed in both tumor and endothelial cells, while NPY was predominantly expressed in neuroblastoma cells. In summary, Y2R is a promising new target for neuroblastoma therapy affecting both cancer cells and tumor vasculature.
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影响因子：
3
作者：
Lee, EW;Grant, DS;Zukowska, Z
通讯作者：
Zukowska, Z
影响因子：
15.9
作者：
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通讯作者：
Zukowska, Z
DOI：
10.1073/pnas.0438011100
发表时间：
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影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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通讯作者：
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影响因子：
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作者：
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