Expression of angiogenic factors vascular endothelial growth factor and interleukin-8/CXCL8 is highly responsive to ambient glutamine availability:: Role of nuclear Factor-κB and activating protein-1
Expression of angiogenic factors vascular endothelial growth factor and interleukin-8/CXCL8 is highly responsive to ambient glutamine availability:: Role of nuclear Factor-κB and activating protein-1
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DOI：
10.1158/0008-5472.can-04-0682
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发表时间：
2004-07-15
期刊：
影响因子：
11.2
通讯作者：
Abcouwer, SF
中科院分区：
文献类型：
--
作者：
Bobrovnikova-Marjon, EV;Marjon, PL;Abcouwer, SF
血管内皮生长因子（VEGF）和白细胞介素-8/CXCL8（IL-8）是显著的促血管生成和促转移蛋白，其在许多类型的癌症中代表负面预后因素。缺氧被认为是实体瘤中VEGF和IL-8表达的主要环境原因。我们假设，除了氧气以外的营养物质的缺乏可以刺激这些因子的表达，并且先前证明VEGF和IL-8的表达对氨基酸剥夺有反应。在本研究中，我们研究了谷氨酰胺可用性对这些因子表达的影响，以及转录因子NF κ B和激活蛋白-1（AP-1）在TSE人乳腺癌细胞对谷氨酰胺剥夺的反应中的作用。VEGF和IL-8的分泌和mRNA水平显着诱导谷氨酰胺剥夺。mRNA的稳定化有助于这种反应。谷氨酰胺剥夺增加NF κ B（p65/p50）和AP-1（Fra-1/c-Jun+JunD）DNA结合活性。用姜黄素阻断NF κ B和AP-1的活化以及显性抑制剂、核因子-κ B（IkappaB）超阻遏物（IkappaBM）的抑制剂和c-Fos的突变形式（A-Fos）的表达表明NF κ B和AP-1转录因子的活化对于诱导IL-8表达是必需的，但对于诱导VEGF表达是不必要的。含有III NF κ B靶基因的宏阵列鉴定了总共17个响应谷氨酰胺剥夺而上调2倍或更多。这些包括生长调节癌基因a（GRO α/GRO 1/CXCL 1），另一种与肿瘤血管生成和转移有关的中性粒细胞化学引诱物。
Vascular endothelial growth factor (VEGF) and interieukin-8/CXCL8 (IL-8) are prominent pro-angiogenic and pro-metastatic proteins that represent negative prognostic factors in many types of cancer. Hypoxia is thought to be the primary environmental cause of VEGF and IL-8 expression in solid tumors. We hypothesized that a lack of nutrients other than oxygen could stimulate the expression of these factors and previously demonstrated that expression of VEGF and IL-8 is responsive to amino acid deprivation. In the present study, we examined the effect of glutamine availability on the expression of these factors as well as the role of transcription factors NFkappaB and activating protein-1 (AP-1) in the response of TSE human breast carcinoma cells to glutamine deprivation. VEGF and IL-8 secretion and mRNA levels were dramatically induced by glutamine deprivation. mRNA stabilization contributed to this response. Glutamine deprivation increased NFkappaB (p65/p50) and AP-1 (Fra-1/c-Jun+JunD) DNA-binding activities. Blocking NFkappaB and AP-1 activation with curcumin as well as expression of dominant inhibitors; inhibitor of nuclear factor-kappaB (IkappaB) super repressor (IkappaBM), and a mutant form of c-Fos (A-Fos) demonstrated that the activation of NFkappaB and AP-1 transcription factors was necessary for the induction of IL-8 expression but dispensable for the induction of VEGF expression. A macro-array containing Ill NFkappaB target genes identified a total of 17 that were up-regulated 2-fold or more in response to glutamine deprivation. These included growth regulated oncogene a (GROalpha/GRO1/CXCL1), another neutrophil chemoattractant implicated in tumor angiogenesis and metastasis.