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@ARTICLE{Stillger:274357,
      author       = {M. N. Stillger and C.-Y. Chen and Z. W. Lai and M. Li and
                      A. Schäfer and A. Pagenstecher and C. Nimsky and J. W.
                      Bartsch and O. Schilling$^*$},
      title        = {{C}hanges in calpain-2 expression during glioblastoma
                      progression predisposes tumor cells to temozolomide
                      resistance by minimizing {DNA} damage and p53-dependent
                      apoptosis.},
      journal      = {Cancer cell international},
      volume       = {23},
      number       = {1},
      issn         = {1475-2867},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2023-00559},
      pages        = {49},
      year         = {2023},
      abstract     = {Glioblastoma multiforme (GBM) is characterized by an
                      unfavorable prognosis for patients affected. During
                      standard-of-care chemotherapy using temozolomide (TMZ),
                      tumors acquire resistance thereby causing tumor recurrence.
                      Thus, deciphering essential molecular pathways causing TMZ
                      resistance are of high therapeutic relevance.Mass
                      spectrometry based proteomics were used to study the GBM
                      proteome. Immunohistochemistry staining of human GBM tissue
                      for either calpain-1 or -2 was performed to locate
                      expression of proteases. In vitro cell based assays were
                      used to measure cell viability and survival of primary
                      patient-derived GBM cells and established GBM cell lines
                      after TMZ ± calpain inhibitor administration. shRNA
                      expression knockdowns of either calpain-1 or calpain-2 were
                      generated to study TMZ sensitivity of the specific subunits.
                      The Comet assay and ɣH2AX signal measurements were
                      performed in order to assess the DNA damage amount and
                      recognition. Finally, quantitative real-time PCR of target
                      proteins was applied to differentiate between
                      transcriptional and post-translational
                      regulation.Calcium-dependent calpain proteases, in
                      particular calpain-2, are more abundant in glioblastoma
                      compared to normal brain and increased in patient-matched
                      initial and recurrent glioblastomas. On the cellular level,
                      pharmacological calpain inhibition increased the
                      sensitivities of primary glioblastoma cells towards TMZ. A
                      genetic knockdown of calpain-2 in U251 cells led to
                      increased caspase-3 cleavage and sensitivity to
                      neocarzinostatin, which rapidly induces DNA strand breakage.
                      We hypothesize that calpain-2 causes desensitization of
                      tumor cells against TMZ by preventing strong DNA damage and
                      subsequent apoptosis via post-translational TP53 inhibition.
                      Indeed, proteomic comparison of U251 control vs. U251
                      calpain-2 knockdown cells highlights perturbed levels of
                      numerous proteins involved in DNA damage response and
                      downstream pathways affecting TP53 and NF-κB signaling.
                      TP53 showed increased protein abundance, but no
                      transcriptional regulation.TMZ-induced cell death in the
                      presence of calpain-2 expression appears to favor DNA repair
                      and promote cell survival. We conclude from our experiments
                      that calpain-2 expression represents a proteomic mode that
                      is associated with higher resistance via 'priming' GBM cells
                      to TMZ chemotherapy. Thus, calpain-2 could serve as a
                      prognostic factor for GBM outcome.},
      keywords     = {Calpain-1 (Other) / Calpain-2 (Other) / DNA damage (Other)
                      / Glioblastoma (Other) / TP53 (Other) / Temozolomide
                      resistance (Other) / U251N (Other)},
      cin          = {FR01},
      ddc          = {610},
      cid          = {I:(DE-He78)FR01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36932402},
      pmc          = {pmc:PMC10022304},
      doi          = {DOI: 10.1186/s12935-023-02889-8},
      url          = {https://inrepo02.dkfz.de/record/274357},
}