% 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{Kumar:284398,
      author       = {A. Kumar and P. Rajasekera and V. Becker and S. Biehn and
                      B. Pérez-Soto and S. Beyer and J. McElroy and A. Becker and
                      B. Johnson and T. Cui and E. Sebastian and A. Grosu$^*$ and
                      S. Lindert and E. H. Bell and H. Manring and J. Haque and A.
                      Chakravarti},
      title        = {{H}ypoxia-{I}nducible {T}ransgelin-2 {C}onfers {T}reatment
                      {R}esistance through {A}ctivation of {PI}3{K}/{A}kt/{GSK}3β
                      {P}athway in {G}lioblastoma.},
      journal      = {International journal of radiation oncology, biology,
                      physics},
      volume       = {117},
      number       = {2S},
      issn         = {0360-3016},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {DKFZ-2023-01987},
      pages        = {e121},
      year         = {2023},
      abstract     = {Glioblastoma (GBM) patients with wild-type IDH experience
                      worse survival response to the standard treatment of surgery
                      followed by radiation therapy (RT) and temozolomide (TMZ)
                      chemotherapy compared to their mutant IDH counterparts. This
                      treatment has remained relatively ineffective partly due to
                      the highly invasive phenotype of GBM leading to therapeutic
                      resistance and tumor recurrence. Hypoxia is one of the key
                      characteristic features of GBM which results in cancer
                      metastasis and confers treatment resistance. Therefore, it
                      is paramount to identify targets to help overcome
                      hypoxia-induced treatment resistance in glioblastoma. Our
                      lab has identified transgelin-2 (TAGLN2) to be significantly
                      upregulated in IDH-wt GBM through multiple molecular
                      profiling studies. This study aims to understand the
                      mechanisms by which TAGLN2 confers treatment resistance for
                      developing additional treatments for GBM. Additionally,
                      active drug development efforts are also underway to target
                      TAGLN2 for circumventing these therapeutic resistance
                      mechanisms for effective GBM therapy.RNAi-mediated TAGLN2
                      knockdown (KD) approach was employed to assess the functions
                      of TAGLN2 in GBM patient-derived xenograft (PDX) cell lines.
                      Series of in vitro functional assays were performed to
                      assess the role of TAGLN2 in these cell lines. Cell
                      proliferation, invasion ± RT and/or TMZ were assessed by
                      MTS and Trans-well invasion assays. Subsequently, WB
                      analysis of oncogenic signaling pathways was performed
                      following Transgelin-2 KD. Co-IP assays and Biacore/SPR
                      analyses were performed to study the binding affinity and
                      kinetics for the interaction of PTEN with TAGLN2. Further,
                      cells were intracranially implanted in nude mice to assess
                      the role of TAGLN2 on tumor growth in vivo.Conditional KD of
                      TAGLN2 reduces cell proliferation, survival and invasive
                      potential of GBM PDX cell lines. TAGLN2 KD also improved the
                      sensitivity of these cells to both TMZ and radiation in
                      vitro, as assessed by proliferation, survival, clonal
                      expansion, and invasion. Histopathological studies of human
                      GBM tumors and mouse xenograft tumors showed elevated
                      expression of TAGLN2 in the peri-necrotic region of the
                      tumors indicating that TAGLN2 protein level was upregulated
                      by hypoxia. We also show that TAGLN2 is induced in hypoxic
                      microenvironments with GBM PDX cell lines and its
                      overexpression may enhance cellular resistance towards
                      conventional therapy. Subsequently, we also show that
                      hypoxia-induced TAGLN2 activates the PI3K/Akt oncogenic
                      pathway through binding and inhibition of PTEN. Finally, in
                      vivo data using an orthotopic xenograft mouse model shows
                      reduction of tumor growth with knockdown of TAGLN2.Our in
                      vitro and in vivo xenograft studies suggest that TAGLN2
                      confers treatment resistance to GBM contributing to tumor
                      recurrence. Altogether, TAGLN2 may serve as a potential
                      therapeutically vulnerable target in GBM specifically
                      through its role in cell survival and invasion.},
      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:37784671},
      doi          = {10.1016/j.ijrobp.2023.06.910},
      url          = {https://inrepo02.dkfz.de/record/284398},
}