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@ARTICLE{Avenhaus:302113,
      author       = {A. Avenhaus$^*$ and B. Kuhn$^*$ and M. Velimirović$^*$ and
                      T. Strobel$^*$ and J. Bulkescher$^*$ and C. Lohrey$^*$ and
                      J. Krijgsveld$^*$ and F. Hoppe-Seyler$^*$ and K.
                      Hoppe-Seyler$^*$},
      title        = {{P}leiotropic {E}ffects of {M}etformin on the
                      {C}hemotherapy {R}esponse of {HPV}-{P}ositive {C}ancer
                      {C}ells.},
      journal      = {Journal of medical virology},
      volume       = {97},
      number       = {6},
      issn         = {0146-6615},
      address      = {Bognor Regis [u.a.]},
      publisher    = {Wiley},
      reportid     = {DKFZ-2025-01245},
      pages        = {e70434},
      year         = {2025},
      note         = {#EA:D365#LA:D365# Z999},
      abstract     = {Improved treatment strategies for HPV-positive cancers are
                      urgently required. The viral E6/E7 oncoproteins are
                      essential for the proliferation of HPV-positive cancer cells
                      and considered attractive therapeutic targets. Metformin is
                      proposed to be repurposed for cancer therapy, but this is
                      under controversial debate. We previously demonstrated that
                      E6/E7 expression and the proliferation of HPV-positive
                      cancer cells are repressed by Metformin. Here, we explore
                      the effects of Metformin on the phenotype of HPV-positive
                      cancer cells in detail, either applied as monotreatment or
                      in combination with chemotherapeutic agents. We provide
                      evidence that the downregulation of E6/E7 is not the primary
                      mechanism underlying Metformin's growth-inhibitory effect in
                      HPV-positive cancer cells. Specifically, compared to
                      targeted E6/E7 repression by RNA interference (RNAi),
                      Metformin treatment differently altered the expression of
                      growth regulatory proteins, exerted different effects on the
                      cell cycle, and was able to suppress growth even in the
                      presence of E6/E7. Furthermore, we found that cancer cells
                      pre-treated with Metformin become resistant to senescence
                      induction by the pro-senescent chemotherapeutic agent
                      Etoposide, likely as a secondary effect of Metformin-induced
                      growth inhibition. Finally, depending on experimental
                      conditions, we uncover divergent, even opposing, effects on
                      the proliferation of HPV-positive cancer cells when
                      Metformin is combined with Cisplatin, with p53 playing a key
                      role in these processes. Collectively, our results show that
                      Metformin exerts complex effects on the phenotype of
                      HPV-positive cancer cells, which are critically influenced
                      by experimental conditions. Our findings may also explain
                      the discrepant results in the literature, reporting
                      agonistic or antagonistic effects upon combining Metformin
                      with Cisplatin.},
      keywords     = {Metformin: pharmacology / Humans / Oncogene Proteins,
                      Viral: genetics / Oncogene Proteins, Viral: metabolism /
                      Cell Line, Tumor / Antineoplastic Agents: pharmacology /
                      Cell Proliferation: drug effects / Papillomavirus
                      Infections: virology / Papillomavirus E7 Proteins: genetics
                      / Etoposide: pharmacology / Female / Metformin (Other) /
                      cervical cancer (Other) / chemotherapy (Other) / human
                      papillomavirus (HPV) (Other) / oncogenesis (Other) /
                      oncoproteins (Other) / Metformin (NLM Chemicals) / Oncogene
                      Proteins, Viral (NLM Chemicals) / Antineoplastic Agents (NLM
                      Chemicals) / Papillomavirus E7 Proteins (NLM Chemicals) /
                      Etoposide (NLM Chemicals)},
      cin          = {D365 / B230},
      ddc          = {610},
      cid          = {I:(DE-He78)D365-20160331 / I:(DE-He78)B230-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40522309},
      pmc          = {pmc:PMC12169209},
      doi          = {10.1002/jmv.70434},
      url          = {https://inrepo02.dkfz.de/record/302113},
}