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@ARTICLE{Ansari:132455,
      author       = {S. S. Ansari$^*$ and A. K. Sharma$^*$ and H. Soni$^*$ and
                      D. M. Ali$^*$ and B. Tews$^*$ and R. König and H. Eibl and
                      M. Berger$^*$},
      title        = {{I}nduction of {ER} and mitochondrial stress by the
                      alkylphosphocholine erufosine in oral squamous cell
                      carcinoma cells.},
      journal      = {Cell death $\&$ disease},
      volume       = {9},
      number       = {3},
      issn         = {2041-4889},
      address      = {London [u.a.]},
      publisher    = {Nature Publishing Group},
      reportid     = {DKFZ-2018-00143},
      pages        = {296},
      year         = {2018},
      abstract     = {Endoplasmic reticulum (ER) plays an essential role in cell
                      function and survival. Accumulation of unfolded or misfolded
                      proteins in the lumen of the ER activates the unfolded
                      protein response (UPR), resulting in ER stress and
                      subsequent apoptosis. The alkylphosphocholine erufosine is a
                      known Akt-mTOR inhibitor in oral squamous cell carcinoma
                      (OSCC). In the present study, we evaluate erufosine's role
                      to induce ER and mitochondrial stress leading to autophagy,
                      apoptosis, and ROS induction. The cellular toxicity of
                      erufosine was determined in two OSCC cell lines and gene
                      expression and enrichment analyses were performed. A
                      positive enrichment of ER stress upon erufosine exposure was
                      observed, which was verified at protein levels for the ER
                      stress sensors and their downstream mediators. Knockdown and
                      pharmacological inhibition of the ER stress sensors PERK and
                      XBP1 revealed their involvement into erufosine's cellular
                      effects, including proliferation, apoptosis, and autophagy
                      induction. Autophagy was confirmed by increased acidic
                      vacuoles and LC3-B levels. Upon erufosine exposure, calcium
                      influx into the cytoplasm of the two OSCC cell lines was
                      seen. Apoptosis was confirmed by nuclear staining,
                      Annexin-V, and immunoblotting of caspases. The induction of
                      mitochondrial stress upon erufosine exposure was predicted
                      by gene set enrichment analysis (GSEA) and shown by
                      erufosine's effect on mitochondrial membrane potential, ATP,
                      and ROS production in OSCC cells. These data show that ER
                      and mitochondrial targeting by erufosine represents a new
                      facet of its mechanism of action as well as a promising new
                      framework in the treatment of head and neck cancers.},
      cin          = {G401 / V077},
      ddc          = {570},
      cid          = {I:(DE-He78)G401-20160331 / I:(DE-He78)V077-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29463797},
      doi          = {10.1038/s41419-018-0342-2},
      url          = {https://inrepo02.dkfz.de/record/132455},
}