Abstract LB-155: Smad4 negatively regulates beta-catenin signaling through proteasomal degradation of Aurora A in human cancer cells

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Aurora kinase A (AURKA), a centrosomal serine/threonine protein kinase, is frequently over-expressed in a wide range of human cancers. In the present study, we showed that the expression of AURKA is downregulated in human cancer cells upon over-expression of the tumor suppressor protein Smad4. Bimolecular Fluorescence Complementation (BiFC) assay revealed that full-length Smad4 and linker region interacts with C terminal (kinase domain) domain of AURKA. Ectopic expression of Smad4 down-regulated the expression of AURKA and attenuated phosphorylation of glycogen synthase kinase-3β (GSK3β) at serine-9 residue in HeLa and AGS cells, which resulted in the reduced protein expression and the transcriptional activity of β-catenin. Pre-incubation with MG132 abrogated the degradation rate of AURKA in Smad4 over-expressing HeLa and AGS cells. Conversely, silencing of Smad4 in HeLa cells up-regulated the expression of AURKA and inactivated GSK3β, and subsequently increased the expression of β-catenin. In addition, transient over-expression of Smad4 in Smad4-deficient SW480 colon cancer cells diminished the expression of AURKA and negated GSK3β phosphorylation, resulting in the reduced protein expression and the transcriptional activity of β-catenin. In contrast, siRNA-mediated silencing of AURKA in Smad4 over-expressed cells failed to alter the expression of β-catenin. Taken together, our study demonstrates that restoration of Smad4 inhibits tumor progression by blocking AURKA -mediated signaling. 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-155. doi:1538-7445.AM2012-LB-155