This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bobrovnikova-Marjon, E. V. Articles by Abcouwer, S. F. Search for Related Content PubMed PubMed Citation Articles by Bobrovnikova-Marjon, E. V. Articles by Abcouwer, S. F.

Expression of Angiogenic Factors Vascular Endothelial Growth Factor and Interleukin-8/CXCL8 Is Highly Responsive to Ambient Glutamine Availability

Role of Nuclear Factor-B and Activating Protein-1

¹ Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, and ² University of New Mexico Cancer Research and Treatment Center, Albuquerque, New Mexico

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 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 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 up-regulated 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.

This article has been cited by other articles:

				M. Philippova, D. Ivanov, M. B. Joshi, E. Kyriakakis, K. Rupp, T. Afonyushkin, V. Bochkov, P. Erne, and T. J. Resink Identification of Proteins Associating with Glycosylphosphatidylinositol- Anchored T-Cadherin on the Surface of Vascular Endothelial Cells: Role for Grp78/BiP in T-Cadherin-Dependent Cell Survival Mol. Cell. Biol., June 15, 2008; 28(12): 4004 - 4017. [Abstract] [Full Text] [PDF]

				D. Dong, M. Ni, J. Li, S. Xiong, W. Ye, J. J. Virrey, C. Mao, R. Ye, M. Wang, L. Pen, et al. Critical Role of the Stress Chaperone GRP78/BiP in Tumor Proliferation, Survival, and Tumor Angiogenesis in Transgene-Induced Mammary Tumor Development Cancer Res., January 15, 2008; 68(2): 498 - 505. [Abstract] [Full Text] [PDF]

				X. Wang, Q. Wang, K. L. Ives, and B. M. Evers Curcumin Inhibits Neurotensin-Mediated Interleukin-8 Production and Migration of HCT116 Human Colon Cancer Cells. Clin. Cancer Res., September 15, 2006; 12(18): 5346 - 5355. [Abstract] [Full Text] [PDF]

				R. E. Schweppe, T. H. Cheung, and N. G. Ahn Global Gene Expression Analysis of ERK5 and ERK1/2 Signaling Reveals a Role for HIF-1 in ERK5-mediated Responses J. Biol. Chem., July 28, 2006; 281(30): 20993 - 21003. [Abstract] [Full Text] [PDF]

				M. Moscova, D. J. Marsh, and R. C. Baxter Protein Chip Discovery of Secreted Proteins Regulated by the Phosphatidylinositol 3-Kinase Pathway in Ovarian Cancer Cell Lines Cancer Res., February 1, 2006; 66(3): 1376 - 1383. [Abstract] [Full Text] [PDF]

				J. Xie, H. Pan, S. Yoo, and S.-J. Gao Kaposi's Sarcoma-Associated Herpesvirus Induction of AP-1 and Interleukin 6 during Primary Infection Mediated by Multiple Mitogen-Activated Protein Kinase Pathways J. Virol., December 15, 2005; 79(24): 15027 - 15037. [Abstract] [Full Text] [PDF]

				S. J. Kwon and Y. J. Lee Effect of Low Glutamine/Glucose on Hypoxia-Induced Elevation of Hypoxia-Inducible Factor-1{alpha} in Human Pancreatic Cancer MiaPaCa-2 and Human Prostatic Cancer DU-145 Cells Clin. Cancer Res., July 1, 2005; 11(13): 4694 - 4700. [Abstract] [Full Text] [PDF]

				D. J. Brat, A. C. Bellail, and E. G. Van Meir The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis Neuro-oncol, April 1, 2005; 7(2): 122 - 133. [Abstract] [PDF]

				K. C. Liboni, N. Li, P. O. Scumpia, and J. Neu Glutamine Modulates LPS-Induced IL-8 Production through I{kappa}B/NF-{kappa}B in Human Fetal and Adult Intestinal Epithelium J. Nutr., February 1, 2005; 135(2): 245 - 251. [Abstract] [Full Text] [PDF]