Amino Acid Deprivation Promotes Tumor Angiogenesis through the GCN2/ATF4 Pathway
As tumors continue to grow and exceed their blood supply, nutrients become limited leading to deficiencies in amino acids (AAD), glucose (GD), and oxygen (hypoxia). These alterations result in significant changes in gene expression. While tumors have been shown to overcome the stress associated with...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-08-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558613801029 |
| _version_ | 1818395190054879232 |
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| author | Yugang Wang Yu Ning Goleeta N Alam Brandon M Jankowski Zhihong Dong Jacques E Nör Peter J Polverini |
| author_facet | Yugang Wang Yu Ning Goleeta N Alam Brandon M Jankowski Zhihong Dong Jacques E Nör Peter J Polverini |
| author_sort | Yugang Wang |
| collection | DOAJ |
| description | As tumors continue to grow and exceed their blood supply, nutrients become limited leading to deficiencies in amino acids (AAD), glucose (GD), and oxygen (hypoxia). These alterations result in significant changes in gene expression. While tumors have been shown to overcome the stress associated with GD or hypoxia by stimulating vascular endothelial growth factor (VEGF)-mediated angiogenesis, the role of AAD in tumor angiogenesis remains to be elucidated. We found that in human tumors, the expression of the general control non-derepressible 2 (GCN2, an AAD sensor) kinase is elevated at both protein and mRNA levels. In vitro studies revealed that VEGF expression is universally induced by AAD treatment in all five cell lines tested (five of five). This is in contrast to two other angiogenesis mediators interleukin-6 (two of five) and fibroblast growth factor 2 (two of five) that have a more restricted expression. Suppressing GCN2 expression significantly decreased AAD-induced VEGF expression. Silencing activating transcription factor 4 (ATF4), a downstream transcription factor of the GCN2 signaling pathway, is also associated with strong inhibition of AAD-induced VEGF expression. PKR-like kinase, the key player in GD-induced unfolded protein response is not involved in this process. In vivo xenograft tumor studies in nonobese diabetic/severe combined immunodeficient mice confirmed that knockdown of GCN2 in tumor cells retards tumor growth and decreases tumor blood vessel density. Our results reveal that the GCN2/ATF4 pathway promotes tumor growth and angiogenesis through AAD-mediated VEGF expression and, thus, is a potential target in cancer therapy. |
| first_indexed | 2024-12-14T06:13:09Z |
| format | Article |
| id | doaj.art-647244be3f9b4e898db841a0b9220739 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-14T06:13:09Z |
| publishDate | 2013-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-647244be3f9b4e898db841a0b92207392022-12-21T23:14:05ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022013-08-0115898999710.1593/neo.13262Amino Acid Deprivation Promotes Tumor Angiogenesis through the GCN2/ATF4 PathwayYugang Wang0Yu Ning1Goleeta N Alam2Brandon M Jankowski3Zhihong Dong4Jacques E Nör5Peter J Polverini6Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MIDepartment of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MIDepartment of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MIDepartment of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MIDepartment of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MIDepartment of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MIDepartment of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MIAs tumors continue to grow and exceed their blood supply, nutrients become limited leading to deficiencies in amino acids (AAD), glucose (GD), and oxygen (hypoxia). These alterations result in significant changes in gene expression. While tumors have been shown to overcome the stress associated with GD or hypoxia by stimulating vascular endothelial growth factor (VEGF)-mediated angiogenesis, the role of AAD in tumor angiogenesis remains to be elucidated. We found that in human tumors, the expression of the general control non-derepressible 2 (GCN2, an AAD sensor) kinase is elevated at both protein and mRNA levels. In vitro studies revealed that VEGF expression is universally induced by AAD treatment in all five cell lines tested (five of five). This is in contrast to two other angiogenesis mediators interleukin-6 (two of five) and fibroblast growth factor 2 (two of five) that have a more restricted expression. Suppressing GCN2 expression significantly decreased AAD-induced VEGF expression. Silencing activating transcription factor 4 (ATF4), a downstream transcription factor of the GCN2 signaling pathway, is also associated with strong inhibition of AAD-induced VEGF expression. PKR-like kinase, the key player in GD-induced unfolded protein response is not involved in this process. In vivo xenograft tumor studies in nonobese diabetic/severe combined immunodeficient mice confirmed that knockdown of GCN2 in tumor cells retards tumor growth and decreases tumor blood vessel density. Our results reveal that the GCN2/ATF4 pathway promotes tumor growth and angiogenesis through AAD-mediated VEGF expression and, thus, is a potential target in cancer therapy.http://www.sciencedirect.com/science/article/pii/S1476558613801029 |
| spellingShingle | Yugang Wang Yu Ning Goleeta N Alam Brandon M Jankowski Zhihong Dong Jacques E Nör Peter J Polverini Amino Acid Deprivation Promotes Tumor Angiogenesis through the GCN2/ATF4 Pathway Neoplasia: An International Journal for Oncology Research |
| title | Amino Acid Deprivation Promotes Tumor Angiogenesis through the GCN2/ATF4 Pathway |
| title_full | Amino Acid Deprivation Promotes Tumor Angiogenesis through the GCN2/ATF4 Pathway |
| title_fullStr | Amino Acid Deprivation Promotes Tumor Angiogenesis through the GCN2/ATF4 Pathway |
| title_full_unstemmed | Amino Acid Deprivation Promotes Tumor Angiogenesis through the GCN2/ATF4 Pathway |
| title_short | Amino Acid Deprivation Promotes Tumor Angiogenesis through the GCN2/ATF4 Pathway |
| title_sort | amino acid deprivation promotes tumor angiogenesis through the gcn2 atf4 pathway |
| url | http://www.sciencedirect.com/science/article/pii/S1476558613801029 |
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