Dataset Information

IFN-? and TNF-?-induced GBP-1 inhibits epithelial cell proliferation through suppression of ?-catenin/TCF signaling.

ABSTRACT: Proinflammatory cytokines induce guanylate-binding protein 1 (GBP-1) protein expression in intestinal epithelial tissues. GBP-1 has been described as influencing a number of cellular processes important for epithelial homeostasis, including cell proliferation. However, many questions remain as to the role of GBP-1 in intestinal mucosal homeostasis. We therefore sought to investigate the function of proinflammatory cytokine-induced GBP-1 during intestinal epithelial cell proliferation. Through the use of complementary GBP-1 overexpression and small interfering RNA-mediated knockdown studies, we now show that GBP-1 acts to inhibit pro-mitogenic ?-catenin/T cell factor (TCF) signaling. Interestingly, proinflammatory cytokine-induced GBP-1 was found to be a potent suppressor of ?-catenin protein levels and ?-catenin serine 552 phosphorylation. Neither glycogen synthase kinase 3? nor proteasomal inhibition alleviated GBP-1-mediated suppression of cell proliferation or ?-catenin/TCF signaling, indicating a non-canonical mechanism of ?-catenin inhibition. Together, these data show that cytokine-induced GBP-1 retards cell proliferation by forming a negative feedback loop that suppresses ?-catenin/TCF signaling.

SUBMITTER: Capaldo CT

PROVIDER: S-EPMC3481006 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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IFN-γ and TNF-α-induced GBP-1 inhibits epithelial cell proliferation through suppression of β-catenin/TCF signaling.

Capaldo C T CT Beeman N N Hilgarth R S RS Nava P P Louis N A NA Naschberger E E Stürzl M M Parkos C A CA Nusrat A A

Mucosal immunology 20120613 6

Proinflammatory cytokines induce guanylate-binding protein 1 (GBP-1) protein expression in intestinal epithelial tissues. GBP-1 has been described as influencing a number of cellular processes important for epithelial homeostasis, including cell proliferation. However, many questions remain as to the role of GBP-1 in intestinal mucosal homeostasis. We therefore sought to investigate the function of proinflammatory cytokine-induced GBP-1 during intestinal epithelial cell proliferation. Through th ...[more]

PMID: 22692453

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Project description:Osteosarcoma, a highly metastasizing bone neoplasm, is a leading cause of death and disability in children and adolescents worldwide. Osteosarcoma is only suboptimally responsive to surgery and radio- and chemotherapy, that too with adverse side effects. Hence, there is a necessary need for safer alternative therapeutic approaches. This study evaluated the anticancer effects of the semi-synthetic compound, pterostilbene-isothiocyanate (PTER-ITC), on human osteosarcoma MG-63 cells through cytotoxicity, wound-healing, and transwell-migration assays. Results showed that PTER-ITC specifically inhibited the survival, proliferation, and migration of osteosarcoma cells. PTER-ITC induced apoptosis in MG-63 cells by disrupting mitochondrial membrane potential, as evident from the outcomes of different cytological staining. The antimetastatic potential of PTER-ITC was evaluated through immunostaining, RT-qPCR, and immunoblotting. In silico (molecular docking and dynamic simulation) and, subsequently, biochemical [co-immunoprecipitation (Co-IP) and luciferase reporter] assays deciphered the underlying mode-of-action of this compound. PTER-ITC increased E-cadherin and reduced N-cadherin levels, thereby facilitating the reversal of epithelial-mesenchymal transition (EMT). It also modulated the expressions of proliferative cell nuclear antigen (PCNA), caspase-3, poly [ADP-ribose] polymerase (PARP-1) and matrix metalloproteinase-2/9 (MMPs-2/9) at transcriptional and translational levels. PTER-ITC interfered with the β-catenin/transcription factor-4 (TCF-4) interaction in silico by occupying the β-catenin binding site on TCF-4, confirmed by their reduced physical interactions (Co-IP assay). This inhibited transcriptional activation of TCF-4 by β-catenin (as shown by luciferase reporter assay). In conclusion, PTER-ITC exhibited potent anticancer effects in vitro against human osteosarcoma cells by abrogating the β-catenin/TCF-4 interaction. Altogether, this study suggests that PTER-ITC may be regarded as a new approach for osteosarcoma treatment.

Dataset Information

IFN-? and TNF-?-induced GBP-1 inhibits epithelial cell proliferation through suppression of ?-catenin/TCF signaling.

Publications

IFN-γ and TNF-α-induced GBP-1 inhibits epithelial cell proliferation through suppression of β-catenin/TCF signaling.

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