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@ARTICLE{Lorenz:300111,
      author       = {N. I. Lorenz$^*$ and B. Sauer$^*$ and H. Urban$^*$ and
                      J.-B. Weinem$^*$ and B. S. Parmar and P. S. Zeiner$^*$ and
                      M. I. Strecker$^*$ and D. Schulte and M. Mittelbronn and T.
                      Alekseeva and L. Sevenich$^*$ and P. N. Harter and C. Münch
                      and J. P. Steinbach$^*$ and A.-L. Luger$^*$ and D. H.
                      Heiland and M. W. Ronellenfitsch},
      title        = {{AMP}-activated protein kinase mediates adaptation of
                      glioblastoma cells to conditions of the tumor
                      microenvironment.},
      journal      = {Journal of experimental $\&$ clinical cancer research},
      volume       = {44},
      number       = {1},
      issn         = {0392-9078},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2025-00609},
      pages        = {104},
      year         = {2025},
      abstract     = {AMP-activated protein kinase (AMPK) is an energy sensor
                      that regulates cellular metabolic activity. We hypothesized
                      that in glioblastoma (GB), AMPK plays a pivotal role in
                      balancing metabolism under conditions of the tumor
                      microenvironment with fluctuating and often low nutrient and
                      oxygen availability. Impairment of this network could thus
                      interfere with tumor progression. AMPK activity was
                      modulated genetically by CRISPR/Cas9-based double knockout
                      (DKO) of the catalytic α1 and α2 subunits in human GB
                      cells and effects were confirmed by pharmacological AMPK
                      inhibition using BAY3827 and an inactive control compound in
                      primary GB cell cultures. We found that metabolic adaptation
                      of GB cells under energy stress conditions (hypoxia, glucose
                      deprivation) was dependent on AMPK and accordingly that AMPK
                      DKO cells were more vulnerable to glucose deprivation or
                      inhibition of glycolysis and sensitized to hypoxia-induced
                      cell death. This effect was rescued by reexpression of the
                      AMPK α2 subunit. Similar results were observed using the
                      selective pharmacological AMPK inhibitor BAY3827.
                      Mitochondrial biogenesis was regulated AMPK-dependently with
                      a reduced mitochondrial mass and mitochondrial membrane
                      potential in AMPK DKO GB cells. In vivo, AMPK DKO GB cells
                      showed impaired tumor growth and tumor formation in CAM
                      assays as well as in an orthotopic glioma mouse model. Our
                      study highlights the importance of AMPK for GB cell
                      adaptation towards energy depletion and emphasizes the role
                      of AMPK for tumor formation in vivo. Moreover, we identified
                      mitochondria as central downstream effectors of AMPK
                      signaling. The development of AMPK inhibitors could open
                      opportunities for the treatment of hypoxic tumors.},
      keywords     = {Glioblastoma: pathology / Glioblastoma: genetics /
                      Glioblastoma: metabolism / Humans / AMP-Activated Protein
                      Kinases: metabolism / Tumor Microenvironment / Animals /
                      Mice / Cell Line, Tumor / Mitochondria: metabolism / Brain
                      Neoplasms: pathology / Brain Neoplasms: genetics / Brain
                      Neoplasms: metabolism / Gene Knockout Techniques /
                      AMP-activated protein kinase (Other) / AMPK (Other) /
                      Glioblastoma (Other) / Hypoxia (Other) / Metabolic
                      adaptation (Other) / AMP-Activated Protein Kinases (NLM
                      Chemicals)},
      cin          = {FM01},
      ddc          = {610},
      cid          = {I:(DE-He78)FM01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40122814},
      doi          = {10.1186/s13046-025-03346-2},
      url          = {https://inrepo02.dkfz.de/record/300111},
}