A Small ?-Carboline Derivative "B-9-3" Modulates TGF-? Signaling Pathway Causing Tumor Regression in Vivo.
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ABSTRACT: Targeting tumor microenvironment (TME) is crucial in order to overcome the anti-cancer therapy resistance. In this study, we report the antitumor activity of a newly synthesized ?-carboline derivative "B-9-3." Here, this small molecule showed a promising antitumor activity in vivo along with an enhanced immune response as reflected by a reduction of regulatory T cells and increased CD4+/CD8+ T cells. Further, B-9-3 decreased the number of myofibroblasts not only in the tumor but also in the lung suggesting an anti-metastatic action. The reduction of myofibroblasts was associated with lower expression of epithelial-to-mesenchymal transition markers and a decrease of phosphorylated SMAD2/3 complex indicating the implication of TGF-? signaling pathway in B-9-3's effect. The blockade of myofibroblasts induction by B-9-3 was also verified in vitro in human fibroblasts treated with TGF-?. To elucidate the mechanism of B-9-3's action on TGF-? pathway, first, we investigated the molecular interaction between B-9-3 and TGF-? receptors using docking method. Data showed a weak interaction of B-9-3 with the ATP-binding pocket of TGF?RI but a strong one with a ternary complex formed of extracellular domains of TGF?RI, TGF?RII, and TGF-?. In addition, the role of TGF?RI and TGF?RII in B-9-3's activity was explored in vitro. B-9-3 did not decrease any of the two receptors' protein level and only reduced phosphorylated SMAD2/3 suggesting that its effect was more probably due to its interaction with the ternary complex rather than decreasing the expression of TGF-? receptors or interfering with their ATP-binding domains. B-9-3 is a small active molecule which acts on the TGF-? signaling pathway and improves the TME to inhibit the proliferation and the metastasis of the tumor with the potential for clinical application.
SUBMITTER: Zhong H
PROVIDER: S-EPMC6063040 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
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