Vascular endothelial growth factor (VEGF) and interleukin-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

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... ivation. 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 NFB 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 NFB (p65/p50) and AP-1 (Fra-1/c-Jun؉JunD) DNA-binding activities. Blocking NFB and AP-1 activation with curcumin as well as expression of dominant inhibitors, inhibitor of nuclear factor-B (IB) super repressor (IBM), and a mutant form of c-Fos (A-Fos) demonstrated that the activation of NFB 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 111 NFB target genes identified a total of 17 that were upregulated 2-fold or more in response to glutamine deprivation. These included growth regulated oncogene ␣ (GRO␣/GRO1/CXCL1), another neutrophil chemoattractant implicated in tumor angiogenesis and metastasis.