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@ARTICLE{Kotredes:862731,
      author       = {Kotredes, Kevin P. and Razmpour, Roshanak and Lutton, Evan
                      and Alfonso-Prieto, Mercedes and Ramirez, Servio H. and
                      Gamero, Ana M.},
      title        = {{C}haracterization of cancer-associated {IDH}2 mutations
                      that differ in tumorigenicity, chemosensitivity and
                      2-hydroxyglutarate production},
      journal      = {OncoTarget},
      volume       = {10},
      number       = {28},
      issn         = {1949-2553},
      address      = {[S.l.]},
      publisher    = {Impact Journals LLC},
      reportid     = {FZJ-2019-02974},
      pages        = {2675-2692},
      year         = {2019},
      abstract     = {The family of isocitrate dehydrogenase (IDH) enzymes is
                      vital for cellular metabolism, as IDH1 and IDH2 are required
                      for the decarboxylation of isocitrate to α-ketoglutarate.
                      Heterozygous somatic mutations in IDH1 or IDH2 genes have
                      been detected in many cancers. They share the neomorphic
                      production of the oncometabolite (R)-2-hydroxyglutarate
                      [(R)-2-HG]. With respect to IDH2, it is unclear whether all
                      IDH2 mutations display the same or differ in tumorigenic
                      properties and degrees of chemosensitivity. Here, we
                      evaluated the three most frequent IDH2 mutations occurring
                      in cancer. The predicted changes to the enzyme structure
                      introduced by these individual mutations are supported by
                      the observed production of (R)-2-HG. However, their
                      tumorigenic properties, response to chemotherapeutic agents,
                      and baseline activation of STAT3 differed. Paradoxically,
                      the varying levels of endogenous (R)-2-HG produced by each
                      IDH2 mutant inversely correlated with their respective
                      growth rates. Interestingly, while we found that (R)-2-HG
                      stimulated the growth of non-transformed cells, (R)-2-HG
                      also displayed antitumor activity by suppressing the growth
                      of tumors harboring wild type IDH2. The mitogenic effect of
                      (R)-2-HG in immortalized cells could be switched to
                      antiproliferative by transformation with oncogenic RAS.
                      Thus, our findings show that despite their shared (R)-2-HG
                      production, IDH2 mutations are not alike and differ in
                      shaping tumor cell behavior and response to chemotherapeutic
                      agents. Our study also reveals that under certain
                      conditions, (R)-2-HG has antitumor properties.},
      cin          = {IAS-5 / INM-9},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {899 - ohne Topic (POF3-899)},
      pid          = {G:(DE-HGF)POF3-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31105869},
      doi          = {10.18632/oncotarget.26848},
      url          = {https://juser.fz-juelich.de/record/862731},
}