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Redirecting TGF-? Signaling through the ?-Catenin/Foxo Complex Prevents Kidney Fibrosis.

ABSTRACT: TGF-? is a key profibrotic factor, but targeting TGF-? to prevent fibrosis also abolishes its protective anti-inflammatory effects. Here, we investigated the hypothesis that we can redirect TGF-? signaling by preventing downstream profibrotic interaction of ?-catenin with T cell factor (TCF), thereby enhancing the interaction of ?-catenin with Foxo, a transcription factor that controls differentiation of TGF-? induced regulatory T cells (iTregs), and thus, enhance anti-inflammatory effects of TGF-? In iTregs derived from EL4 T cells treated with recombinant human TGF-?1 (rhTGF-?1) in vitro, inhibition of ?-catenin/TCF transcription with ICG-001 increased Foxp3 expression, interaction of ?-catenin and Foxo1, binding of Foxo1 to the Foxp3 promoter, and Foxo transcriptional activity. Moreover, the level of ?-catenin expression positively correlated with the level of Foxo1 binding to the Foxp3 promoter and Foxo transcriptional activity. T cell fate mapping in Foxp3gfp Ly5.1/5.2 mice revealed that coadministration of rhTGF-?1 and ICG-001 further enhanced the expansion of iTregs and natural Tregs observed with rhTGF-?1 treatment alone. Coadministration of rhTGF-?1 with ICG-001 also increased the number of Tregs and reduced inflammation and fibrosis in the kidney fibrosis models of unilateral ureteric obstruction and ischemia-reperfusion injury. Notably, ICG-001 prevented the fibrosis in distant organs (lung and liver) caused by rhTGF-?1. Together, our results show that diversion of ?-catenin from TCF- to Foxo-mediated transcription inhibits the ?-catenin/TCF-mediated profibrotic effects of TGF-? while enhancing the ?-catenin/Foxo-mediated anti-inflammatory effects. Targeting ?-catenin/Foxo may be a novel therapeutic strategy in the treatment of fibrotic diseases that lead to organ failure.

SUBMITTER: Qiao X

PROVIDER: S-EPMC5791062 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Redirecting TGF-β Signaling through the β-Catenin/Foxo Complex Prevents Kidney Fibrosis.

Qiao Xi X Rao Padmashree P Zhang Yun Y Liu Lixin L Pang Min M Wang Hailong H Hu Min M Tian Xinrui X Zhang Jianlin J Zhao Ye Y Wang Xin Maggie XM Wang Chengshi C Yu Hong H Guo Fei F Cao Qi Q Wang Yiping Y Wang Yuan Min YM Zhang Geoff Yu GY Lee Vincent W VW Alexander Stephen I SI Zheng Guoping G Harris David C H DCH

Journal of the American Society of Nephrology : JASN 20171127 2

TGF-β is a key profibrotic factor, but targeting TGF-β to prevent fibrosis also abolishes its protective anti-inflammatory effects. Here, we investigated the hypothesis that we can redirect TGF-β signaling by preventing downstream profibrotic interaction of β-catenin with T cell factor (TCF), thereby enhancing the interaction of β-catenin with Foxo, a transcription factor that controls differentiation of TGF-β induced regulatory T cells (iTregs), and thu ...[more]

PMID: 29180394

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Project description:Mammary tumorigenesis is associated with the increased expression of several proteins in the focal adhesion complex, including focal adhesion kinase (FAK) and various integrins. Aberrant expression of these molecules occurs concomitant with the conversion of TGF-beta function from a tumor suppressor to a tumor promoter. We previously showed that interaction between beta3 integrin and TbetaR-II facilitates TGF-beta-mediated oncogenic signaling, epithelial-mesenchymal transition (EMT), and metastasis. However, the molecular mechanisms by which the focal adhesion complex contributes to beta3 integrin:TbetaR-II signaling and the oncogenic conversion of TGF-beta remain poorly understood.FAK expression and activity were inhibited in normal and malignant mammary epithelial cells (MECs) either genetically by using lentiviral-mediated delivery of shRNAs against FAK, or pharmacologically through in vitro and in vivo use of the FAK inhibitors, PF-562271 and PF-573228. Altered Smad2/3 and p38 MAPK activation, migration, EMT, and invasion in response to TGF-beta1 were monitored in FAK-manipulated cells. TbetaR-II expression was increased in metastatic breast cancer cells by retroviral transduction, and the metastasis of FAK- and TbetaR-II-manipulated tumors was monitored by using bioluminescent imaging.TGF-beta stimulation of MECs stabilized and activated FAK in a beta3 integrin- and Src-dependent manner. Furthermore, by using the human MCF10A breast cancer progression model, we showed that increased FAK expression in metastatic breast cancer cells mirrored the acquisition of enhanced activation of p38 MAPK by TGF-beta. Administering FAK inhibitors or rendering metastatic breast cancer cells FAK deficient abrogated the interaction between beta3 integrin and TbetaR-II, thereby preventing TGF-beta from (a) activating p38 MAPK; (b) stimulating MEC invasion, migration, and EMT; and (c) inducing early primary tumor dissemination to the lungs. Finally, in contrast to FAK depletion, adjuvant FAK chemotherapy of mammary tumors decreased their growth in part by diminished macrophage tumor infiltration.Our studies identify an essential function for FAK in mediating the interaction between beta3 integrin and TbetaR-II, and thus in facilitating the oncogenic conversion of TGF-beta required for mammary tumor metastasis. Furthermore, this study establishes chemotherapeutic targeting of FAK as an effective, two-pronged approach in preventing tumor progression both by decreasing innate immune cell infiltration, and by inhibiting early TGF-beta-dependent metastasis.

Dataset Information

Redirecting TGF-? Signaling through the ?-Catenin/Foxo Complex Prevents Kidney Fibrosis.

Publications

Redirecting TGF-<i>β</i> Signaling through the <i>β</i>-Catenin/Foxo Complex Prevents Kidney Fibrosis.

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