Acute L-glutamine deprivation compromises VEGF-a upregulation in A549/8 human carcinoma cells.
Tumor ischemia participates in angiogenesis and cancer progression through cellular responses to hypoxia and nutrient deprivation. However, the contribution of amino acids limitation to this process remains poorly understood. Using serum-free cell culture conditions, we tested the impact of L-glutamine deprivation on metabolic and angiogenic responses in A549/8 carcinoma cells. In these cells, lowering glutamine concentration modified the cell cycle distribution and significantly induced apoptosis/necrosis. Although glutamine deprivation led to a HIF-independent increase in VEGF-A mRNA, the corresponding protein level remained low and correlated with the inhibition of protein synthesis and activation of the GCN2/eIF2alpha pathway. Limitation of glutamine availability also hampers hypoxia- and hypoglycemia-induced VEGF-A protein upregulation. Thus, glutamine deprivation may have no direct effect on VEGF-dependent angiogenesis, compared to hypoxia or to glucose deprivation, and may instead be detrimental to cancer progression by antagonizing ischemia-induced stresses.
Drogat
Benjamin
B
INSERM, E0113, Université Bordeaux 1, Talence, France.
Bouchecareilh
Marion
M
North
Sophie
S
Petibois
Cyril
C
Déléris
Gérard
G
Chevet
Eric
E
Bikfalvi
Andréas
A
Moenner
Michel
M
D000601:Amino Acids, Essential / Q000378:metabolism; D017209:Apoptosis; D002453:Cell Cycle; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016895:Culture Media, Serum-Free / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000172:deficiency; D005973:Glutamine / Q000172:deficiency*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009336:Necrosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D000601:Amino Acids, Essential; D016895:Culture Media, Serum-Free; D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D005973:Glutamine; D017346:Protein Serine-Threonine Kinases; D005947:Glucose