Abstract
Abstract β-catenin is a key downstream effector in the Wnt signaling pathway. It is implicated in two major biological processes in vertebrates: early embryonic development and tumorigenesis. The receptor for advanced glycation endproducts (RAGE), a member of the immunoglobulin superfamily of cell membrane receptors, is encoded within the MHC Class III Region. It interacts with various ligands including high mobility group protein 1 [HMGB1], certain S100 protein family members, and advanced glycation endproducts and is involved in cancer, inflammation, diabetes and Alzheimer disease. To evaluate whether treatment with RAGE short hairpin RNA (shRNA) increases chemosensitivity in pancreatic cancers involves β-catenin signaling, we first examined the expression level of β-catenin and its target genes. In normal states, β-catenin and its target genes cyclinD1, c-myc, and Nr-CAM but not L1CAM were decreased when RAGE was depleted in the murine Panc02 cell line by western blot and immunofluorescence analysis. Importantly, RAGE deletion enhanced the suppressive effects of chemotherapy on the expression of β-catenin and its target genes. To evaluate the effects of β-catenin on chemosensitivity in pancreatic cancer cells, we used cells in which the expression of RAGE and/or β-catenin was suppressed by shRNA. Knockdown of β-catenin increased chemosensitivity in pancreatic cancer cells and these effects were enhanced when both β-catenin and RAGE were knocked down. Notably, knockdown of β-catenin had no effect on the commitment of cells to enhanced autophagic flux when assessed by evaluation of microtubule-associated protein 1 light chain 3 (LC3) punctae formation. However, knockdown of β-catenin did significantly increase apoptosis when assayed by increased activity of caspase 3 and cleavage of caspase3. Taken together, these results suggest that RAGE regulates β-catenin transcription function and chemosensitivity in pancreatic cancer cell lines. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4674.
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