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A Small ?-Carboline Derivative "B-9-3" Modulates TGF-? Signaling Pathway Causing Tumor Regression in Vivo.

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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A Small β-Carboline Derivative "B-9-3" Modulates TGF-β Signaling Pathway Causing Tumor Regression <i>in Vivo</i>.

Zhong Hui H Daoud Abdelkader A Han Jichun J An Xiaohong X Qiao Caili C Duan Lanlan L Wang Yichuan Y Chen Zhenfeng Z Zhou Jia J Shang Jing J

Frontiers in pharmacology 20180719

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 β-carboline derivative "B-9-3." Here, this small molecule showed a promising antitumor activity <i>in vivo</i> 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 t ...[more]

PMID: 30079021

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Project description:Breast cancer progression and metastasis have been linked to abnormal signaling by transforming growth factor-? (TGF-?) cytokines. In early-stage breast cancers, TGF-? exhibits tumor suppressor activity by repressing cell proliferation and inducing cell death, whereas in advanced-stage tumors, TGF-? promotes invasion and metastatic dissemination. The molecular mechanisms underlying pro-oncogenic activities of TGF-? are not fully understood. The present study validates the role of TGF-? signaling in cancer progression and explores mediators of pro-oncogenic TGF-? activities using the LM3 mammary adenocarcinoma cell line, derived from a spontaneous murine mammary adenocarcinoma. Expression of kinase-inactive TGF-? receptors decreased both basal and TGF-?-induced invasion. Analysis of signal transduction mediators showed that p38MAPK and MEK contribute to TGF-? stimulation of cell motility and invasion. TGF-? disrupted the epithelial actin structures supporting cell-cell adhesions, and increased linear actin filaments. Moreover, MEK and p38MAPK pathways showed opposite effects on actin remodeling in response to TGF-?. Blockade of Raf-MEK signaling enhanced TGF-? induction of actin stress-fibers whereas p38MAPK inhibitors blocked this effect. A novel observation was made that TGF-? rapidly activates the actin nucleation Arp2/3 complex. In addition, TGF-? stimulated matrix metalloproteinase MMP-9 secretion via a MAPK-independent pathway. Experiments using syngeneic mice showed that kinase-inactive TGF-? receptors inhibit the first stages of LM3 tumor growth in vivo. Our studies demonstrate that autocrine TGF-? signaling contributes to the invasive behavior of mammary carcinoma cells. Moreover, we show that both MAPK-dependent and -independent pathways are necessary for TGF-?-induced effects. Therefore, MEK-ERK and p38 MAPK pathways are potential venues for therapeutic intervention in pro-oncogenic TGF-? signaling.

Dataset Information

A Small ?-Carboline Derivative "B-9-3" Modulates TGF-? Signaling Pathway Causing Tumor Regression in Vivo.

Publications

A Small β-Carboline Derivative "B-9-3" Modulates TGF-β Signaling Pathway Causing Tumor Regression <i>in Vivo</i>.

Similar Datasets

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