% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Knoll:128918,
      author       = {M. Knoll$^*$ and S. Macher-Goeppinger$^*$ and J. Kopitz$^*$
                      and S. Duensing and S. Pahernik and M. Hohenfellner and P.
                      Schirmacher and W. Roth$^*$},
      title        = {{T}he ribosomal protein {S}6 in renal cell carcinoma:
                      functional relevance and potential as biomarker.},
      journal      = {OncoTarget},
      volume       = {7},
      number       = {1},
      issn         = {1949-2553},
      address      = {[S.l.]},
      publisher    = {Impact Journals LLC},
      reportid     = {DKFZ-2017-04931},
      pages        = {418 - 432},
      year         = {2016},
      abstract     = {Inhibitors of the mTOR pathway, such as everolimus, are
                      promising compounds to treat patients with renal cell
                      carcinomas (RCCs). However, the precise mechanisms of action
                      are far from clear, and biomarkers predicting the response
                      to mTOR inhibitors are still missing. Here, we provide
                      evidence that in RCCs the rpS6 protein is the major mediator
                      of anti-tumoral effects exerted by everolimus. Inhibition of
                      mTOR signaling results in substantially decreased
                      clonogenicity and proliferation of RCC cells, but did not
                      significantly induce apoptosis. Everolimus effectively
                      blocked protein biosynthesis both in vitro and in a novel ex
                      vivo tissue slice model using fresh vital human RCC tissue.
                      Compared to other components of the mTOR pathway,
                      phosphorylation of rpS6 was most effectively downregulated
                      by everolimus. Importantly, siRNA-mediated downregulation of
                      rpS6, but not of 4ebp1 or p27, abolished the inhibitory
                      effects of everolimus on proliferation and protein
                      synthesis. Moreover, we analyzed the tissue expression of
                      phosphorylated rpS6 (p-rpS6) and non-phosphorylated rpS6 in
                      a large collection of patients with RCCs (n=598 and n=548,
                      respectively). Expression of both proteins qualified as
                      independent negative prognostic markers with a substantially
                      shorter survival of patients with RCCs exhibiting high
                      levels of rpS6 and p-rpS6. Taken together, our functional
                      studies identified rpS6 as a main mediator of the
                      anti-tumoral activity of Everolimus. Therefore, further
                      (pre-)clinical evaluations of rpS6 as a predictive marker
                      for everolimus-based treatment for RCC patients are
                      warranted. Finally, the combined detection of phosphorylated
                      and non-phosphorylated rpS6 could represent a robust
                      prognostic marker to identify patients with high risk RCCs.},
      keywords     = {Antineoplastic Agents (NLM Chemicals) / Biomarkers, Tumor
                      (NLM Chemicals) / Ribosomal Protein S6 (NLM Chemicals) /
                      Everolimus (NLM Chemicals)},
      cin          = {G150 / G105},
      ddc          = {610},
      cid          = {I:(DE-He78)G150-20160331 / I:(DE-He78)G105-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26506236},
      pmc          = {pmc:PMC4808008},
      doi          = {10.18632/oncotarget.6225},
      url          = {https://inrepo02.dkfz.de/record/128918},
}