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@ARTICLE{Heber:285976,
      author       = {N. Heber$^*$ and B. Kuhn$^*$ and T. D. Strobel$^*$ and C.
                      Lohrey$^*$ and J. Krijgsveld$^*$ and K. Hoppe-Seyler$^*$ and
                      F. Hoppe-Seyler$^*$},
      title        = {{T}he impact of cycling hypoxia on the phenotype of
                      {HPV}-positive cervical cancer cells.},
      journal      = {Journal of medical virology},
      volume       = {95},
      number       = {12},
      issn         = {0146-6615},
      address      = {Bognor Regis [u.a.]},
      publisher    = {Wiley},
      reportid     = {DKFZ-2023-02559},
      pages        = {e29280},
      year         = {2023},
      note         = {#EA:F065#LA:F065#},
      abstract     = {Cycling hypoxia (cycH) is a prevalent form of tumor hypoxia
                      that is characterized by exposure of tumor cells to
                      recurrent phases of hypoxia and reoxygenation. CycH has been
                      associated with a particularly aggressive cellular phenotype
                      of tumor cells and increased therapy resistance. By
                      performing comparative analyses under normoxia, physoxia,
                      chronic hypoxia, and cycH, we here uncover distinct effects
                      of cycH on the phenotype of human papillomavirus
                      (HPV)-positive cervical cancer cells. We show that-other
                      than under chronic hypoxia-viral E6/E7 oncogene expression
                      is largely maintained under cycH as is the E6/E7-dependent
                      regulation of p53 and retinoblastoma protein. Further, cycH
                      enables HPV-positive cancer cells to evade prosenescent
                      chemotherapy, similar to chronic hypoxia. Moreover, cells
                      under cycH exhibit a particularly pronounced resistance to
                      the proapoptotic effects of Cisplatin. Quantitative proteome
                      analyses reveal that cycH induces a unique proteomic
                      signature in cervical cancer cells, which includes a
                      significant downregulation of luminal lysosomal proteins.
                      These encompass the potentially proapoptotic cathepsins B
                      and cathepsin L, which, however, appear not to affect the
                      response to Cisplatin under any of the O2 conditions tested.
                      Rather, we show that the proapoptotic Caspase
                      8/BH3-interacting domain death agonist (BID) cascade plays a
                      pivotal role for the efficiency of Cisplatin-induced
                      apoptosis in HPV-positive cancer cells under all
                      investigated O2 conditions. In addition, we provide evidence
                      that BID activation by Cisplatin is impaired under cycH,
                      which could contribute to the high resistance to the
                      proapoptotic effects of Cisplatin. Collectively, this study
                      provides the first insights into the profound phenotypic
                      alterations induced by cycH in HPV-positive cancer cells,
                      with implications for their therapeutic susceptibility.},
      keywords     = {BH3-interacting domain death agonist (Other) / cervical
                      cancer (Other) / chemoresistance (Other) / cisplatin (CDDP)
                      (Other) / human papillomavirus (Other) / hypoxia (Other)},
      cin          = {F065 / B230},
      ddc          = {610},
      cid          = {I:(DE-He78)F065-20160331 / I:(DE-He78)B230-20160331},
      pnm          = {316 - Infektionen, Entzündung und Krebs (POF4-316)},
      pid          = {G:(DE-HGF)POF4-316},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38054507},
      doi          = {10.1002/jmv.29280},
      url          = {https://inrepo02.dkfz.de/record/285976},
}