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 in | PloS one Vol. 8; no. 9; p. e74741 |
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| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
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United States
Public Library of Science
06.09.2013
Public Library of Science (PLoS) |
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| Abstract | 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. |
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| AbstractList | 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. |
| Author | Lehman, Jason A Hauck, Paula M Batuello, Christopher N Gendron, Jaimie M Mayo, Lindsey D Albig, Allan Eitel, Jacob A Kadakia, Madhavi P |
| AuthorAffiliation | 1 Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Indianapolis, Indiana, United States of America Rush University Medical Center, United States of America 4 Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, United States of America 5 Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America 3 Department of Biology; Boise State University, Boise, Idaho, United States of America 2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America |
| AuthorAffiliation_xml | – name: 1 Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Indianapolis, Indiana, United States of America – name: Rush University Medical Center, United States of America – name: 5 Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America – name: 3 Department of Biology; Boise State University, Boise, Idaho, United States of America – name: 2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America – name: 4 Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, United States of America |
| Author_xml | – sequence: 1 givenname: Jason A surname: Lehman fullname: Lehman, Jason A organization: Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Indianapolis, Indiana, United States of America – sequence: 2 givenname: Paula M surname: Hauck fullname: Hauck, Paula M – sequence: 3 givenname: Jaimie M surname: Gendron fullname: Gendron, Jaimie M – sequence: 4 givenname: Christopher N surname: Batuello fullname: Batuello, Christopher N – sequence: 5 givenname: Jacob A surname: Eitel fullname: Eitel, Jacob A – sequence: 6 givenname: Allan surname: Albig fullname: Albig, Allan – sequence: 7 givenname: Madhavi P surname: Kadakia fullname: Kadakia, Madhavi P – sequence: 8 givenname: Lindsey D surname: Mayo fullname: Mayo, Lindsey D |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24040331$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_2147_OTT_S244409 crossref_primary_10_2147_OTT_S260376 crossref_primary_10_1146_annurev_pathol_012414_040349 crossref_primary_10_18632_oncotarget_13951 crossref_primary_10_1186_s40064_015_1406_8 crossref_primary_10_1016_j_tiv_2020_104908 crossref_primary_10_1038_s41589_023_01349_8 |
| Cites_doi | 10.1158/1535-7163.MCT-10-0337 10.1158/0008-5472.CAN-06-2710 10.1093/carcin/bgp196 10.1101/gad.14.1.34 10.1016/j.canlet.2011.08.011 10.1016/j.cell.2006.05.036 10.1002/1097-0142(20000601)88:11<2606::AID-CNCR25>3.0.CO;2-W 10.1007/s10456-011-9210-8 10.1128/MCB.24.7.2905-2914.2004 10.1074/jbc.M110.217620 10.1158/1078-0432.CCR-11-1101 10.1016/S0968-0004(98)01344-9 10.1002/jcp.20406 10.1158/1535-7163.MCT-05-0356 10.5483/BMBRep.2011.44.3.158 |
| ContentType | Journal Article |
| Copyright | 2013 Lehman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2013 Lehman et al 2013 Lehman et al |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 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. |
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| References_xml | – volume: 9 start-page: 2545 year: 2010 ident: ref6 article-title: The novel tryptamine derivative JNJ-26854165 induces wild-type p53- and E2F1-mediated apoptosis in acute myeloid and lymphoid leukemias publication-title: Mol Cancer Ther doi: 10.1158/1535-7163.MCT-10-0337 contributor: fullname: K Kojima – volume: 67 start-page: 450 year: 2007 ident: ref4 article-title: Nutlin3 blocks vascular endothelial growth factor induction by preventing the interaction between hypoxia inducible factor 1alpha and Hdm2 publication-title: Cancer Res doi: 10.1158/0008-5472.CAN-06-2710 contributor: fullname: GA LaRusch – volume: 30 start-page: 1768 year: 2009 ident: ref10 article-title: Nutlin-3, an Hdm2 antagonist, inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated inactivation of HIF-1alpha publication-title: Carcinogenesis doi: 10.1093/carcin/bgp196 contributor: fullname: YM Lee – volume: 14 start-page: 34 year: 2000 ident: ref1 article-title: Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha publication-title: Genes Dev doi: 10.1101/gad.14.1.34 contributor: fullname: R Ravi – volume: 312 start-page: 209 year: 2011 ident: ref7 article-title: Preclinical assessment of JNJ-26854165 (Serdemetan), a novel tryptamine compound with radiosensitizing activity in vitro and in tumor xenografts publication-title: Cancer Lett doi: 10.1016/j.canlet.2011.08.011 contributor: fullname: C Chargari – volume: 126 start-page: 107 year: 2006 ident: ref15 article-title: TIGAR, a p53-inducible regulator of glycolysis and apoptosis publication-title: Cell doi: 10.1016/j.cell.2006.05.036 contributor: fullname: K Bensaad – volume: 88 start-page: 2606 year: 2000 ident: ref13 article-title: Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression publication-title: Cancer doi: 10.1002/1097-0142(20000601)88:11<2606::AID-CNCR25>3.0.CO;2-W contributor: fullname: D Zagzag – volume: 14 start-page: 255 year: 2011 ident: ref14 article-title: Effect of MDM2 and vascular endothelial growth factor inhibition on tumor angiogenesis and metastasis in neuroblastoma publication-title: Angiogenesis doi: 10.1007/s10456-011-9210-8 contributor: fullname: DM Patterson – volume: 24 start-page: 2905 year: 2004 ident: ref5 article-title: Growth factor-mediated induction of HDM2 positively regulates hypoxia-inducible factor 1alpha expression publication-title: Mol Cell Biol doi: 10.1128/MCB.24.7.2905-2914.2004 contributor: fullname: JI Bardos – volume: 286 start-page: 36631 year: 2011 ident: ref8 article-title: Induction of apoptotic genes by a p73-phosphatase and tensin homolog (p73-PTEN) protein complex in response to genotoxic stress publication-title: J Biol Chem doi: 10.1074/jbc.M110.217620 contributor: fullname: JA Lehman – volume: 17 start-page: 6313 year: 2011 ident: ref12 article-title: A phase I first-in-human pharmacokinetic and pharmacodynamic study of serdemetan in patients with advanced solid tumors publication-title: Clin Cancer Res doi: 10.1158/1078-0432.CCR-11-1101 contributor: fullname: J Tabernero – volume: 24 start-page: 68 year: 1999 ident: ref2 article-title: Oncogenic alterations of metabolism publication-title: Trends Biochem Sci doi: 10.1016/S0968-0004(98)01344-9 contributor: fullname: CV Dang – volume: 204 start-page: 364 year: 2005 ident: ref3 article-title: Mdm2 and HIF-1alpha interaction in tumor cells during hypoxia publication-title: J Cell Physiol doi: 10.1002/jcp.20406 contributor: fullname: AL Nieminen – volume: 5 start-page: 411 year: 2006 ident: ref9 article-title: Radiosensitization of lung cancer by nutlin, an inhibitor of murine double minute 2 publication-title: Mol Cancer Ther doi: 10.1158/1535-7163.MCT-05-0356 contributor: fullname: C Cao – volume: 44 start-page: 158 year: 2011 ident: ref11 article-title: Glioblastoma multiforme: a perspective on recent findings in human cancer and mouse models publication-title: BMB Rep doi: 10.5483/BMBRep.2011.44.3.158 contributor: fullname: SK Lim |
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| Snippet | 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... |
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| SubjectTerms | 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 |
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| Title | Serdemetan antagonizes the Mdm2-HIF1α axis leading to decreased levels of glycolytic enzymes |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/24040331 https://www.proquest.com/docview/1430904356 https://search.proquest.com/docview/1433267120 https://pubmed.ncbi.nlm.nih.gov/PMC3765416 https://doaj.org/article/7275d8cc4eaa42faa9106b18ff10b8e3 http://dx.doi.org/10.1371/journal.pone.0074741 |
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