VEGF receptor expression and signaling in human bladder tumors
VEGF receptor expression and signaling in human bladder tumors
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DOI：
10.1038/sj.onc.1206285
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发表时间：
2003-05-29
期刊：
影响因子：
8
通讯作者：
Broek, D
中科院分区：
文献类型：
--
作者：
Wu, WC;Shu, XD;Broek, D
血管内皮生长因子受体（VEGFRs）的过表达已经在多种肿瘤类型中被报道。在这里，我们发现14种膀胱肿瘤细胞中有11种表达一种或多种VEGF受体。对T24膀胱肿瘤细胞系的分析揭示了一个涉及VEGF和Flk-1受体的功能性自分泌环。阻断T24细胞中VEGF表达导致DNA合成减少。T24细胞中的Flk-1受体在VEGF-121或VEGF-165的作用下发生磷酸化，Flk-1抑制剂阻断VEGF对ERK信号的传递。我们报道，VEGF刺激T24细胞导致H- ras和N-Ras的激活，这依赖于细胞鞘氨酸激酶I （SPK1）的活性。先前，我们发现vegf诱导的Ras激活似乎不依赖于Ras-鸟嘌呤核苷酸交换因子（GEFs）。本文报道了鞘氨醇在体外可以刺激Ras-GTPase激活蛋白（GAP）活性，而鞘氨醇- i -磷酸（SPP）可以阻断鞘氨醇的刺激作用。我们提出了一个模型，其中鞘氨醇和SPP之间的平衡调节Ras- gap活性，这样SPK1的刺激有利于Ras- gap的下调，从而激活Ras蛋白。这些数据强调了VEGF通路可能参与膀胱肿瘤细胞以及其他肿瘤细胞类型的存活和增殖。
Overexpression of vascular endothelial growth factor receptors (VEGFRs) has been reported in a variety of tumor types. Here we find that 11 out of the 14 bladder tumor cell tines examined express one or more VEGF receptors. Analysis of the T24 bladder tumor cell line reveals a functional autocrine loop involving VEGF and the Flk-1 receptor. Blocking VEGF expression in T24 cells results in a decrease in DNA synthesis. The Flk-1 receptor in T24 cells is phosphorylated in response to VEGF-121 or VEGF-165, and an Flk-1 inhibitor blocks VEGF to ERK signaling. We report that VEGF stimulation of T24 cells results in activation of H- and N-Ras and this is dependent on cellular sphingosine kinase I (SPK1) activity. Previously, we found VEGF-induced activation of Ras appears to be independent of a Ras-guanine nucleotide exchange factors (GEFs). Here we report that sphingosine can stimulate Ras-GTPase activating protein (GAP) activity in vitro, and sphingosine-I-phosphate (SPP) can block the stimulatory effects of sphingosine. We present a model where the balance between sphingosine and SPP regulates Ras-GAP activity such that stimulation of SPK1 favors downregulation of Ras-GAP and thereby the activation of Ras proteins. These data highlight a VEGF pathway that may be involved in the survival and proliferation of bladder tumor cells as well as other tumor cell types.