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@ARTICLE{Biedermann:148854,
      author       = {J. Biedermann and M. Preussler and M. Conde and M. Peitzsch
                      and S. Richter and R. Wiedemuth and K. Abou-El-Ardat and A.
                      Krüger$^*$ and M. Meinhardt and G. Schackert$^*$ and W. P.
                      Leenders and C. Herold-Mende and S. P. Niclou and R.
                      Bjerkvig and G. Eisenhofer and A. Temme$^*$ and M. Seifert
                      and L. A. Kunz-Schughart and E. Schröck$^*$ and B.
                      Klink$^*$},
      title        = {{M}utant {IDH}1 {D}ifferently {A}ffects {R}edox {S}tate and
                      {M}etabolism in {G}lial {C}ells of {N}ormal and {T}umor
                      {O}rigin.},
      journal      = {Cancers},
      volume       = {11},
      number       = {12},
      issn         = {2072-6694},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2020-00046},
      pages        = {2028},
      year         = {2019},
      abstract     = {IDH1R132H (isocitrate dehydrogenase 1) mutations play a key
                      role in the development of low-grade gliomas. IDH1wt
                      converts isocitrate to α-ketoglutarate while reducing
                      nicotinamide adenine dinucleotide phosphate (NADP+), whereas
                      IDH1R132H uses α-ketoglutarate and NADPH to generate the
                      oncometabolite 2-hydroxyglutarate (2-HG). While the effects
                      of 2-HG have been the subject of intense research, the 2-HG
                      independent effects of IDH1R132H are still ambiguous. The
                      present study demonstrates that IDH1R132H expression but not
                      2-HG alone leads to significantly decreased tricarboxylic
                      acid (TCA) cycle metabolites, reduced proliferation, and
                      enhanced sensitivity to irradiation in both glioblastoma
                      cells and astrocytes in vitro. Glioblastoma cells, but not
                      astrocytes, showed decreased NADPH and NAD+ levels upon
                      IDH1R132H transduction. However, in astrocytes IDH1R132H led
                      to elevated expression of the NAD-synthesizing enzyme
                      nicotinamide phosphoribosyltransferase (NAMPT). These
                      effects were not 2-HG mediated. This suggests that IDH1R132H
                      cells utilize NAD+ to restore NADP pools, which only
                      astrocytes could compensate via induction of NAMPT. We found
                      that the expression of NAMPT is lower in patient-derived
                      IDH1-mutant glioma cells and xenografts compared to
                      IDH1-wildtype models. The Cancer Genome Atlas (TCGA) data
                      analysis confirmed lower NAMPT expression in IDH1-mutant
                      versus IDH1-wildtype gliomas. We show that the IDH1 mutation
                      directly affects the energy homeostasis and redox state in a
                      cell-type dependent manner. Targeting the impairments in
                      metabolism and redox state might open up new avenues for
                      treating IDH1-mutant gliomas.},
      cin          = {L301},
      ddc          = {610},
      cid          = {I:(DE-He78)L301-20160331},
      pnm          = {899 - ohne Topic (POF3-899)},
      pid          = {G:(DE-HGF)POF3-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31888244},
      doi          = {10.3390/cancers11122028},
      url          = {https://inrepo02.dkfz.de/record/148854},
}