In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. LB-209-LB-209
Abstract:
Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumors. The aggressive and highly invasive phenotype of these tumors makes them among the more destructive human cancers with a median survival of less than one year. In the different GBM tumor subtypes several altered genes and multiple pathways cooperate to promote and sustain tumor growth, tumor invasion and tumor recurrence. Although Wnt pathway activation was historically linked to the presence of mutations involving key components of the network (APC, β-catenin or AXIN proteins), an increasing number of studies suggest that aberrant Wnt signaling can also be initiated by several alternative mechanisms. Autocrine signaling mediated by specific Wnt ligands has been linked to lung, breast and pancreatic tumours, but also malignant melanoma cells spreading. Wnt signals, both positive and negative, form a class of paracrine growth factors that could act to influence multiple myeloma cell growth, metastatic potential and target tissue erosion. Although very well studied in multiple diseases, the role and importance of Wnt signaling pathway has not been extensively described in GBM tumors. After an initial phase where we showed modulation of the Wnt transcriptional activity and the phenotypic consequences of negative Wnt signaling after β-catenin KO in glioma cells we started a screening campaign to identify small molecules Wnt inhibitors coupling a pathway/phenotypic approach to oncology relevant phenotypic assays. Among the different chemical classes identified, we characterized a selective canonical Wnt signaling inhibitor, which stabilizes axin (a negative regulator of the Wnt signalling pathway) at the protein level together with a concomitant decrease at the transcriptional level. Due to the central role of axin in controlling the ratio between the unphosphorylated (the stable form which can then enter the nucleus and thus activate Wnt target genes) and the phosphorylated (labelled for proteasomal degradation) pool of β-catenin we also observed as a consequence an increase in the amount of cytosolic phosphorylated β-catenin (S33/S37/T41) and a decrease of total β-catenin. One possible explanation for the up-regulation of axin protein level and the concomitant decrease of steady-state axin mRNA levels after compound treatment could be via a protein stabilization mechanism, as demonstrated by the effects of the small molecule on the half-life of axin2 in DBTRG cells. Consistent with a protective effect of the molecule against axin2 proteasomal degradation, co-treatment of the Wnt inhibitor and the reversible proteasome inhibitor MG-132 almost completely blocked the ubiquitination of axin2. In vivo studies, used to confirm the in vitro observations, showed antitumor activity in a glioma xenograft model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-209. doi:1538-7445.AM2012-LB-209
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2012-LB-209
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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