VEGF and Bcl-2 interact via MAPKs signaling pathway in the response to hypoxia in neuroblastoma.
Tumor hypoxia has been reported to be a negative prognostic factor in a number of tumor sites, which suggests a positive correlation between tumor hypoxia and increased metastatic efficiency. Evidence shows that vascular endothelial growth factor (VEGF) stimulates angiogenesis in tumor growth and mediates neuroprotection to prevent an apoptotic cell death. Human neuroblastoma cells (CHP126) were exposed to moderate hypoxia for different time spans to explore the molecular stress responses. Apoptotic features as an increase of Bax/Bcl-2 ratio and activation of caspase 3 were observed at early period of exposure time, but these effects were reversed with the extension of hypoxic treatment. Hypoxia also activated MAPKs signaling pathways in a time-relative manner, which were involved in the regulation of hypoxia-related resistance of CHP126 cells. Meanwhile, VEGF and its receptor KDR were found to interact with MAPKs signaling pathways except the effect of hypoxia. Furthermore, rhVEGF(165) was utilized to discern that VEGF increased Bcl-2 and procaspase 3 expressions, contributing to a synergistic relationship of an angiogenic response with Bcl-2 in hypoxia via a cross talk, while the activation of ERK MAPK is important for both productions. These altered signals may be critical to predict a poor outcome; therefore, our knowledge provides new insight into apoptosis and angiogenesis control of tumor cells and suggests a strategy based on the blockade of hypoxia-induced VEGF signaling under hypoxia in neuroblastoma.
Wang
Duoduo
D
Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, 388# Yuhangtang Road, Hangzhou, 310058, China.
Weng
Qinjie
Q
Zhang
Lei
L
He
Qiaojun
Q
Yang
Bo
B
D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D009447:Neuroblastoma / Q000201:enzymology* / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051028:bcl-2-Associated X Protein; D040262:Receptors, Vascular Endothelial Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3