Serdemetan antagonizes the Mdm2-HIF1α axis leading to decreased levels of glycolytic enzymes

Serdemetan (JNJ-26854165), an antagonist to Mdm2, was anticipated to promote the activation of p53. While regulation of p53 by Mdm2 is important, Mdm2 also regulates numerous proteins involved in diverse cellular functions. We investigated if Serdemetan would alter the Mdm2-HIF1α axis and affect cel...

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Published inPloS one Vol. 8; no. 9; p. e74741
Main Authors Lehman, Jason A, Hauck, Paula M, Gendron, Jaimie M, Batuello, Christopher N, Eitel, Jacob A, Albig, Allan, Kadakia, Madhavi P, Mayo, Lindsey D
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 06.09.2013
Public Library of Science (PLoS)
Subjects
Angiogenesis
Apoptosis
Biochemistry
Brain cancer
Brain Neoplasms - enzymology
Cell Line, Tumor - drug effects
Cell Survival
Enzymes
Fluorides
Gene expression
Gene Expression Regulation, Neoplastic
Glioblastoma
Glioblastoma - enzymology
Glioblastoma cells
Glucose transporter
Glycolysis
Humans
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors
MDM2 protein
Medicine
Molecular biology
p53 Protein
Pediatrics
Phosphopyruvate hydratase
Proteins
Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors
Rodents
Side effects
Tryptamines - pharmacology
Tumor Suppressor Protein p53 - metabolism
Tumors
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - metabolism
Indiana
United States > US
Indianapolis Indiana
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Summary:Serdemetan (JNJ-26854165), an antagonist to Mdm2, was anticipated to promote the activation of p53. While regulation of p53 by Mdm2 is important, Mdm2 also regulates numerous proteins involved in diverse cellular functions. We investigated if Serdemetan would alter the Mdm2-HIF1α axis and affect cell survival in human glioblastoma cells independently of p53. Treatment of cells with Serdemetan under hypoxia resulted in a decrease in HIF1α levels. HIF1α downstream targets, VEGF and the glycolytic enzymes (enolase, phosphoglycerate kinase1/2, and glucose transporter 1), were all decreased in response to Serdemetan. The involvement of Mdm2 in regulating gene expression of glycolytic enzymes raises the possibility of side effects associated with therapeutically targeting Mdm2.
Bibliography:ObjectType-Article-1
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Conceived and designed the experiments: LDM. Performed the experiments: JAL PMH JMG JAE CNB LDM. Analyzed the data: MPK AA LDM. Contributed reagents/materials/analysis tools: LDM AA MPK. Wrote the paper: JAL PMH JMG MPK LDM.
Competing Interests: Johnson and Johnson for providing Serdemetan, Riley Children’s Foundation for financial support. J&J only provided the compound under an MTA. The authors followed the guide lines of the MTA with J&J and provided the manuscript for their pre-review. They released the work without any conditions (considering they did not fund the work). This does not alter the authors’ adherence to all PLOS ONE policies on sharing data and materials and the authors have declared that no competing interest exists.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0074741