title: Pancreatic endoplasmic reticulum kinase activation promotes medulloblastoma cell migration and invasion through induction of vascular endothelial growth factor A.
abstract: Evidence is accumulating that activation of the pancreatic endoplasmic reticulum kinase (PERK) in response to endoplasmic reticulum (ER) stress adapts tumor cells to the tumor microenvironment and enhances tumor angiogenesis by inducing vascular endothelial growth factor A (VEGF-A). Recent studies suggest that VEGF-A can act directly on certain tumor cell types in an autocrine manner, via binding to VEGF receptor 2 (VEGFR2), to promote tumor cell migration and invasion. Although several reports show that PERK activation increases VEGF-A expression in medulloblastoma, the most common solid malignancy of childhood, the role that either PERK or VEGF-A plays in medulloblastoma remains elusive. In this study, we mimicked the moderate enhancement of PERK activity observed in tumor patients using a genetic approach and a pharmacologic approach, and found that moderate activation of PERK signaling facilitated medulloblastoma cell migration and invasion and increased the production of VEGF-A. Moreover, using the VEGFR2 inhibitor SU5416 and the VEGF-A neutralizing antibody to block VEGF-A/VEGFR2 signaling, our results suggested that tumor cell-derived VEGF-A promoted medulloblastoma cell migration and invasion through VEGFR2 signaling, and that both VEGF-A and VEGFR2 were required for the promoting effects of PERK activation on medulloblastoma cell migration and invasion. Thus, these findings suggest that moderate PERK activation promotes medulloblastoma cell migration and invasion through enhancement of VEGF-A/VEGFR2 signaling.
authors: Department of Neuroscience, University of Minnesota, Minneapolis, United States of America; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, United States of America.
authors: Stephanie
authors: S
authors: Jamison
authors: Department of Neuroscience, University of Minnesota, Minneapolis, United States of America; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, United States of America.
authors: Yifeng
authors: Y
authors: Lin
authors: Department of Neuroscience, University of Minnesota, Minneapolis, United States of America; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, United States of America; Masonic Cancer Center, University of Minnesota, Minneapolis, United States of America.
authors: Wensheng
authors: W
authors: Lin
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002528:Cerebellar Neoplasms / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C576403:7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine; D007211:Indoles; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; D000225:Adenine