Intracrine VEGF Signaling Mediates the Activity of Prosurvival Pathways in Human Colorectal Cancer Cells.
Intracrine VEGF Signaling Mediates the Activity of Prosurvival Pathways in Human Colorectal Cancer Cells.
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DOI：
10.1158/0008-5472.can-15-1605
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发表时间：
2016-05-15
期刊：
影响因子：
11.2
通讯作者：
Ellis LM
中科院分区：
文献类型：
--
作者：
Bhattacharya R;Ye XC;Wang R;Ling X;McManus M;Fan F;Boulbes D;Ellis LM
血管内皮生长因子-A（VEGF-A/VEGF）及其受体对内皮细胞功能的影响已被广泛研究，但对肿瘤细胞的作用尚不清楚。对VEGF基因缺失的人结直肠癌（CRC）细胞的研究表明VEGF作为细胞存活因子的细胞内作用。在这项研究中，我们研究了大肠癌细胞存活中VEGF信号的作用。在人类CRC细胞中，RNA干扰介导的VEGF缺失降低了细胞存活率并增强了对化疗的敏感性。无偏见的反相蛋白阵列研究和随后的验证实验表明，细胞存活受损是AKT和ERK 1/2（MAPK 3/1）信号传导中断的结果，磷酸化减少即可证明这一点。抑制旁分泌或自分泌VEGF信号传导对磷酸化AKT或磷酸化ERK 1/2水平没有影响，表明VEGF通过细胞内机制介导细胞存活。值得注意的是，RNAi介导的VEGF受体VEGFR 1/FLT 1的耗竭复制了VEGF耗竭对磷酸化AKT和磷酸化ERK 1/2水平的影响。总之，这些研究显示了VEGF如何在CRC细胞中作为一种内分泌存活因子发挥作用，证明了其在CRC细胞存活中的独特作用。
The effects of vascular endothelial growth factor-A (VEGF-A/VEGF) and its receptors on endothelial cells function has been studied extensively, but their effects on tumor cells are less well defined. Studies of human colorectal cancer (CRC) cells where the VEGF gene has been deleted suggest an intracellular role of VEGF as a cell survival factor. In this study, we investigated the role intracrine VEGF signaling in CRC cell survival. In human CRC cells, RNAi-mediated depletion of VEGF decreased cell survival and enhanced sensitivity to chemotherapy. Unbiased reverse phase protein array studies and subsequent validation experiments indicated that impaired cell survival was a consequence of disrupted AKT and ERK1/2 (MAPK3/1) signaling, as evidenced by reduced phosphorylation. Inhibition of paracrine or autocrine VEGF signaling had no effect on phospho-AKT or phospho-ERK1/2 levels, indicating that VEGF mediates cell survival via an intracellular mechanism. Notably, RNAi-mediated depletion of VEGF receptor VEGFR1/FLT1 replicated the effects of VEGF depletion on phospho-AKT and phospho-ERK1/2 levels. Together, these studies show how VEGF functions as an intracrine survival factor in CRC cells, demonstrating its distinct role in CRC cell survival.