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Chemoprevention of B-cell lymphomas by inhibition of the Myc target spermidine synthase
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Jonas Nilsson)
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Jonas Nilsson)
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Jonas Nilsson)
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. Vol. 3, no 2, 140-147 p.
Keyword [en]
Myc, Srm, Odc, polyamines, lymphomagenesis
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-32085DOI: 10.1158/1940-6207.CAPR-09-0166ISI: 000274247000005OAI: oai:DiVA.org:umu-32085DiVA: diva2:300914
Available from: 2010-03-01 Created: 2010-03-01 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Myc-induced Lymphomagenesis: In vivo assessment of downstream pathways
Open this publication in new window or tab >>Myc-induced Lymphomagenesis: In vivo assessment of downstream pathways
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Myc-inducerad lymfomutveckling : Utvärdering av målgener in vivo
Abstract [en]

Myc oncogenes encode transcription factors that bind to E-box sequences in DNA, driving the expression of a large number of target genes and are deregulated in approximately 70% of human cancers. Deregulated Myc expression cause enhanced proliferation (which is counteracted by apoptosis), angiogenesis and cancer. Though Myc’s importance in induction of S phase has been established, less is known about its functions in the G2 and M phases of the cell cycle. Paper I addresses the targeting of the Myc targets Aurora kinase A and B that have roles in G2/M transition and provide evidence that pharmaceutical Aurora kinase inhibition causes cell cycle arrest and apoptosis in a Myc-selective manner and is useful in treating Myc-induced lymphomas in vivo.

The assumption that the important target genes responsible for the biological effects of Myc overexpression were those encoding components of the cell cycle machinery lead to little interest in other potentially important groups of target genes. However, recent work challenged this view by indicating that Myc target genes encoding metabolic enzymes may be critical for Myc-induced tumorigenesis. Importantly, the targeting of Myc target genes encoding metabolic enzymes has the potential of providing a new treatment strategy of Myc-induced cancers. Paper II covers the pharmaceutical targeting of the Myc-induced spermidine synthase (Srm) that shows promise as a tool for chemoprevention by affecting proliferation, but not for the treatment of established tumors.

Paper III focuses on the negligible effect an Ldha mutation has on Myc- induced lymphomagenesis. Ldha has long been known to be a Myc target gene and in vitro experiments have recently indicated it to be important for transformation. It seems the negligible effect of the Ldh mutation can be explained by the high frequency of loss of either Arf or p53 in this mouse model, since enforced Ras-Myc oncogenic cooperation in soft agar assays of Ldh mutant MEFs effectively inhibits colony formation, and λ-Myc;Ldh mutant bone marrow infected with oncogenic Ras does not give rise to tumors when transplanted into wild-type mice. A role for Ldh in the ability of tumors to evade the immune system was also indicated in this study. The combined experiences and very different outcome of the three studies included in this thesis draw attention to the value of in vivo assessment of Myc downstream targets in Myc-induced lymphomagenesis.

Publisher
79 p.
Keyword
Myc, lymphomagenesis, Aurora kinases, polyamine, glycolysis, targeting, mouse models of cancer
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-32093 (URN)978-91-7264-951-4 (ISBN)
Public defence
2010-03-26, Building 6L, Major Groove, Umeå University, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2010-03-05 Created: 2010-03-01 Last updated: 2010-03-05Bibliographically approved
2. Examining the role of metabolism in Myc-driven tumorigenesis
Open this publication in new window or tab >>Examining the role of metabolism in Myc-driven tumorigenesis
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
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:nbn:se:umu:diva-46564 (URN)978-91-7459-284-9 (ISBN)
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

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Plym Forshell, Tacha ZiRimpi, SaraNilsson, Jonas A
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