P10.34.B ONCOGENIC ASPP2KAPPA(K), A DOMINANT-NEGATIVE ISOFORM OF THE APOPTOSIS STIMULATING PROTEIN OF P53-2 (ASPP2) PROMOTES CLASSICAL HALLMARKS OF CANCER IN GLIOBLASTOMA

• DOI: 10.1093/neuonc/noad137.232
• Publication Date: 2023-09-08T15:59:45Z
• Authors: M Hafner; A Ruiba; L Kampa; I Sommer; A Ahrens; V Kälin; A Zeitlberger; K Buchauer; L Plasswilm; T Hundsberger; M Neidert; M M Schittenhelm; K M Kampa-Schitte...
• Keywords: Temozolomide

Abstract BACKGROUND GB is the most common, aggressive primary brain tumor with a deleterious prognosis. ASPP2 suppressor, directly interacting p53. We recently identified dominant-negative isoform of ASPP2, named ASPP2κ, lacking important p53 binding sites and show that ASPP2κ highly expressed functionally active in glioblastoma, affecting all classical hallmarks cancer. MATERIAL AND METHODS Grade IV glioma (n=46) were assessed for expression. Isogenic models, stably suppressing or overexpressing established A-172, U-251 T98g cell lines from resected tissue. The role induction apoptosis, cellular proliferation, migration invasion was vitro vivo. Proteome arrays allowed to study pathways involved signaling. Two knock-down (KD) NOD/SCID xenotransplant mouse models engraftment progression. RESULTS Frequent overexpression confirmed virtually patients analyzed compared tumor-free Expression thereby varied widely between (2-40 fold). Functional analyses confirm affects multiple cancer GB, resulting more phenotype impaired apoptosis (avg. -25 %), higher proliferation +25%), +65%) +70%) rates. Silencing rescues wt suppressor phenotype, rendering cells susceptible towards temozolomide (TMZ, avg. γ-irradiation +40%) combinational approaches. Upregulation phosphorylation (S15: 2,5x/S46: 1,5x) cycle regulators (p21: 2x, p27: 3x pRAD: 2,5x) confirms restoration p53-mediated pathways. attenuated progression KD tumors Mice carrying ASPP2κ-KD presented statistically significant increased overall survival both (p= 0.03 p=0.005) growth (p=0.0001). Importantly, neo-angiogenesis strongly regulated relation expression, impairing metastasis models. Downregulation pro-angiogenic (VEGF 20x, angiogenin 4x) upregulation anti-angiogenic (endostatin LAP players confirmed. CONCLUSION cancer, including regulation cycle, invasion/metastasis angiogenesis. contributes aggressiveness disease resistance therapy silencing re-activates crucial tumorsuppressor Studies evaluating as target are ongoing.