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Examining the role of metabolism in Myc-driven tumorigenesis
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Jonas Nilsson)
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Myc transcriptionally regulates genes involved in processes such as cell proliferation, metabolism, differentiation, and angiogenesis.  MYC expression is deregulated in many types of human cancer; therefore discovering the mechanisms behind MYCs role in tumorigenesis is essential.  In this dissertation, I have focused on several Myc target genes, Spermidine synthase (Srm); Lactate dehydrogenase (Ldh); 3-phosphoglycerate dehydrogenase (Phgdh); Serine hydroxymethyltransferase (SHMT) 1 and 2; and Pim-3 (a member of the Pim family of serine/threonine kinases).  These enzymes play a role in various functions: Spermidine synthase (polyamine synthesis); Lactate dehydrogenase (glycolysis); Phgdh and Shmt (serine metabolism); and Pim-3 (cell signaling).  In order to elucidate the impact Myc over-expression has on metabolism in tumorigenesis, we use human cell lines, and transgenic mice as well as cell lines and tissues derived from these mice.  The impact of inhibition of these target genes on Myc-driven tumorigenesis was done by genetically inhibiting the target gene (using RNAi or mouse models) or inhibiting the protein with a chemical inhibitor.  Investigating these Myc target genes will help determine if inhibition of Myc target genes is a viable approach for chemotherapeutics, and under what conditions this inhibition may be the most valuable.  In paper I, we examine SRM; a highly expressed enzyme in the polyamine synthesis pathway that converts putrescine to spermidine, and is important for actively growing cells.  Genetic inhibition via RNAi against Srm, or chemical inhibition of Srm, resulted in decreased proliferation of B-cell tumor lines from transgenic mice in vitroIn vivo treatment of λ-Myc transgenic mice with a chemical SRM inhibitor exhibited a significant chemopreventative effect on tumor formation. These results support previous findings that inhibition of polyamine synthesis pathway enzymes has a place in cancer therapy.  Many Myc target genes have been suggested as attractive targets in battling Myc-driven tumorigenesis.  Surprisingly in paper II, when we analyzed the inhibition of other Myc target genes, such as Ldh, Shmt, and Phgdh, we found that inhibition of these genes did not inhibit Myc-driven tumorigenesis to any significant degree. However, inhibition of Ldh, Phgdh and Shmt2 had a notable effect on in vitro Ras-driven transformation.  These findings suggest that chemotherapeutic inhibition of metabolic genes such as Ldh, Phgdh and Shmt2 may be effective in genetically defined settings, keeping in mind the oncogenic lesion behind the tumor.  The Pim kinase family consists of three serine/threonine kinases, Pim1-3.  In paper III, we found that Pim-3 is a direct Myc target gene and that Pim-3 expression is high in Burkitt Lymphoma samples taken from human patients, as well as spontaneously arising lymphomas from Myc transgenic mice. We also found that inhibition of Pim-3 using a pan-Pim kinase inhibitor, Pimi, in these spontaneously arising Myc lymphomas resulted in caspase independent cell death.  These results indicate that Pim kinase inhibition may be a potential chemotherapeutic strategy in human lymphomas that rely on Pim-3 kinase expression.

Place, publisher, year, edition, pages
Umeå: Umeå University, Department of Molecular Biology (Faculty of Science and Technology) , 2011. , 56 p.
Keyword [en]
cancer, Myc, metabolism, polyamines, spermidine synthase, glycolysis, lactate dehydrogenase, serine metabolism, Phgdh, folate metabolism, Shmt, Pim kinase, Pim-3 Kinase
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-46564ISBN: 978-91-7459-284-9 (print)OAI: oai:DiVA.org:umu-46564DiVA: diva2:438882
Public defence
2011-10-01, Byggnad 6L, Major Groove, Umeå University, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2011-09-07 Created: 2011-09-05 Last updated: 2011-09-26Bibliographically approved
List of papers
1. Chemoprevention of B-cell lymphomas by inhibition of the Myc target spermidine synthase
Open this publication in new window or tab >>Chemoprevention of B-cell lymphomas by inhibition of the Myc target spermidine synthase
2010 (English)In: Cancer Prevention Research, ISSN 1940-6207, E-ISSN 1940-6215, Vol. 3, no 2, 140-147 p.Article in journal (Refereed) Published
Abstract [en]

The oncogenic transcription factor c-Myc (Myc) is frequently overexpressed in human cancers. Myc is known to induce or repress a large set of genes involved in cell growth and proliferation, explaining the selection for mutations in cancer that deregulate Myc expression. Inhibition of ornithine decarboxylase, an enzyme of the polyamine biosynthetic pathway and a Myc target, has been shown to be chemopreventive. In the present study, we have dissected the role of another enzyme in the polyamine biosynthetic pathway, spermidine synthase (Srm), in Myc-induced cancer. We find that Srm is encoded by a Myc target gene containing perfect E-boxes and that it is induced by Myc in a direct manner. RNA interference against Srm shows that it is important for Myc-induced proliferation of mouse fibroblasts but to a lesser extent for transformation. Using the compound trans-4-methylcyclohexylamine, we show that Srm inhibition can delay the onset of B-cell lymphoma development in λ-Myc transgenic mice. We therefore suggest that inhibition of Srm is an additional chemopreventive strategy that warrants further consideration.

Place, publisher, year, edition, pages
Philadelphia, PA: American Association for Cancer Research, 2010
Keyword
Myc, Srm, Odc, polyamines, lymphomagenesis
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-32085 (URN)10.1158/1940-6207.CAPR-09-0166 (DOI)000274247000005 ()
Available from: 2010-03-01 Created: 2010-03-01 Last updated: 2017-12-12Bibliographically approved
2. Mouse Genetics Suggests Cell-Context Dependency for Myc-Regulated Metabolic Enzymes during Tumorigenesis
Open this publication in new window or tab >>Mouse Genetics Suggests Cell-Context Dependency for Myc-Regulated Metabolic Enzymes during Tumorigenesis
Show others...
2012 (English)In: PLOS Genetics, ISSN 1553-7390, Vol. 8, no 3, e1002573- p.Article in journal (Refereed) Published
Abstract [en]

c-Myc (hereafter called Myc) belongs to a family of transcription factors that regulates cell growth, cell proliferation, and differentiation. Myc initiates the transcription of a large cast of genes involved in cell growth by stimulating metabolism and protein synthesis. Some of these, like those involved in glycolysis, may be part of the Warburg effect, which is defined as increased glucose uptake and lactate production in the presence of adequate oxygen supply. In this study, we have taken a mouse-genetics approach to challenge the role of select Myc-regulated metabolic enzymes in tumorigenesis in vivo. By breeding λ-Myctransgenic mice, ApcMin mice, and p53 knockout mice with mouse models carrying inactivating alleles of Lactate dehydrogenase A (Ldha), 3-Phosphoglycerate dehydrogenase (Phgdh) and Serine hydroxymethyltransferase 1 (Shmt1), we obtained offspring that were monitored for tumor development. Very surprisingly, we found that these genes are dispensable for tumorigenesis in these genetic settings. However, experiments in fibroblasts and colon carcinoma cells expressing oncogenic Ras show that these cells are sensitive to Ldha knockdown. Our genetic models reveal cell context dependency and a remarkable ability of tumor cells to adapt to alterations in critical metabolic pathways. Thus, to achieve clinical success, it will be of importance to correctly stratify patients and to find synthetic lethal combinations of inhibitors targeting metabolic enzymes.

National Category
Cell and Molecular Biology
Research subject
biology; Genetics
Identifiers
urn:nbn:se:umu:diva-46562 (URN)10.1371/journal.pgen.1002573 (DOI)000302254800048 ()
Note
Manuscript version included in thesis had the title "Mouse genetics suggest that metabolic enzymes dispensable for Myc-induced lymphomagenesis can play critical roles for Ras-induced fibrosarcoma growth"Available from: 2011-09-05 Created: 2011-09-05 Last updated: 2012-05-30Bibliographically approved
3. The direct Myc target Pim3 cooperates with other Pim kinases in supporting viability of Myc-induced B-cell lymphomas
Open this publication in new window or tab >>The direct Myc target Pim3 cooperates with other Pim kinases in supporting viability of Myc-induced B-cell lymphomas
Show others...
2011 (English)In: Oncotarget, ISSN 1949-2553, Vol. 2, no 6, 448-460 p.Article in journal (Refereed) Published
Abstract [en]

The Pim kinases are weak oncogenes. However, when co-expressed with a strong oncogene, such as c-Myc, Pim kinases potentiate the oncogenic effect resulting in an acceleration of tumorigenesis. In this study we show that the least studied Pim kinase, Pim-3, is encoded by a gene directly regulated by c-Myc via binding to one of the conserved E-boxes within the Pim3 gene. Accordingly, lymphomas arising in Myc-transgenic mice and Burkitt lymphoma cell lines exhibit elevated levels of Pim-3. Interestingly, inhibition of Pim kinases by a novel pan-Pim kinase inhibitor, Pimi, in Myc-induced lymphoma results in cell death that appears independent of caspases. The data indicate that Pim kinase inhibition could be a viable treatment strategy in certain human lymphomas that rely on Pim-3 kinase expression.

Place, publisher, year, edition, pages
Albany, N.Y.: Impact Journals, 2011
National Category
Biochemistry and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-46326 (URN)10.18632/oncotarget.283 (DOI)000293510200005 ()21646687 (PubMedID)
Available from: 2011-08-30 Created: 2011-08-30 Last updated: 2017-01-17Bibliographically approved

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