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@ARTICLE{Amann:126043,
      author       = {P. M. Amann and K. Czaja and A. V. Bazhin and R. Rühl and
                      S. Eichmüller$^*$ and H. F. Merk and J. M. Baron},
      title        = {{LRAT} overexpression diminishes intracellular levels of
                      biologically active retinoids and reduces retinoid antitumor
                      efficacy in the murine melanoma {B}16{F}10 cell line.},
      journal      = {Skin pharmacology and physiology},
      volume       = {28},
      number       = {4},
      issn         = {1660-5535},
      address      = {Basel},
      publisher    = {Karger},
      reportid     = {DKFZ-2017-02158},
      pages        = {205 - 212},
      year         = {2015},
      abstract     = {Vitamin A (all- trans -retinol, ATRol) serves as a
                      precursor for all- trans -retinoic acid (ATRA), a ligand for
                      the retinoic acid receptor (RAR), representing a potent
                      regulator for many physiological processes. While murine
                      melanoma cells are highly sensitive to retinoid treatment,
                      human melanoma cells have developed still unidentified
                      mechanisms that mediate cellular retinoid resistance. One of
                      the key retinoid metabolizing enzymes is lecithin retinol
                      acyltransferase (LRAT), which catalyzes the transformation
                      of ATRol into inactive retinyl esters. LRAT is highly
                      expressed in human melanoma cells. The aim of this study was
                      to identify the mechanisms in retinol metabolism that are
                      responsible for cellular retinoid sensitivity in the murine
                      melanoma cell line B16F10.mRNA expression analysis, cell
                      viability assessment and determination of intracellular
                      retinoid levels using HPLC analysis of a generated
                      LRAT-overexpressing B16F10 cell line compared to the control
                      B16F10 cell line.We found that the murine retinoid-sensitive
                      B16F10 cell line does not express the enzyme LRAT. LRAT
                      overexpression decreased the antiproliferative effects of
                      retinoid treatment in these melanoma cells. The
                      RAR-regulated enzyme Cyp26a1 showed a significantly lower
                      expression in LRAT-overexpressing B16F10 cells. Cyp26a1
                      expression was restored after ATRA incubation. HPLC analysis
                      revealed that the level of inactive retinyl ester increased
                      after ATRol treatment, and levels of the substrate ATRol and
                      biologically active ATRA significantly decreased in
                      LRAT-overexpressing murine melanoma. Consistently with this,
                      levels of 4-oxoretinoic acid, an ATRA metabolite and Cyp26a1
                      product, were also decreased in LRAT-overexpressing
                      cells.Our results revealed a direct link between LRAT
                      expression and regulation of ATRA levels indicating that the
                      absence of LRAT-catalyzed retinol esterification is
                      important for mediating retinoid sensitivity in murine
                      melanoma cells. Thus, our data suggest that LRAT
                      overexpression represents a novel mechanism by which tumor
                      cells can escape high supplementary ATRA levels that mediate
                      tumor-suppressive RAR signaling.},
      keywords     = {retinal dimer (NLM Chemicals) / Vitamin A (NLM Chemicals) /
                      Tretinoin (NLM Chemicals) / Cytochrome P-450 Enzyme System
                      (NLM Chemicals) / Cyp26a1 protein, mouse (NLM Chemicals) /
                      Retinoic Acid 4-Hydroxylase (NLM Chemicals) /
                      Acyltransferases (NLM Chemicals) / lecithin-retinol
                      acyltransferase (NLM Chemicals) / Retinaldehyde (NLM
                      Chemicals)},
      cin          = {G183},
      ddc          = {610},
      cid          = {I:(DE-He78)G183-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25721651},
      doi          = {10.1159/000368806},
      url          = {https://inrepo02.dkfz.de/record/126043},
}