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Bromoethylindole (BEI-9) redirects NF-?B signaling induced by camptothecin and TNF? to promote cell death in colon cancer cells.

ABSTRACT: Chemotherapeutic regimens containing camptothecin (CPT), 5-fluorouracil, and oxaliplatin are used to treat advanced colorectal cancer. We previously reported that an indole derivative, 3-(2-bromoethyl)indole (BEI-9), inhibited the proliferation of colon cancer cells and suppressed NF-?B activation. Here, we show that a combination of BEI-9 with either CPT or tumor necrosis factor alpha (TNF?) enhances cell death. Using colorectal cancer cells, we examined the activation of NF-?B by drugs, the potential of BEI-9 for inhibiting drug-induced NF-?B activation, and the enhancement of cell death by combination treatments. Cells were treated with the chemotherapeutic drugs alone or in combination with BEI-9. NF-?B activation, cell cycle profiles, DNA-damage response, markers of cell death signaling and targets of NF-?B were evaluated to determine the effects of single and co-treatments. The combination of BEI-9 with CPT or TNF? inhibited NF-?B activation and reduced the expression of NF-?B-responsive genes, Bcl-xL and COX2. Compared to CPT or BEI-9 alone, sequential treatment of the cells with CPT and BEI-9 significantly enhanced caspase activation and cell death. Co-treatment with TNF? and BEI-9 also caused more cytotoxicity than TNF? or BEI-9 alone. Combined BEI-9 and TNF? enhanced cell death through caspase activation and cleavage of the switch-protein, RIP1 kinase. BEI-9 reduced the expression of COX2 both alone and in combination with CPT or TNF. We postulate that BEI-9 enhances the effects of these drugs on cancer cells by turning off or redirecting NF-?B signaling. Therefore, the combination of BEI-9 with drugs that activate NF-?B needs to be evaluated for clinical applications.

SUBMITTER: Chowdhury R

PROVIDER: S-EPMC6005376 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Bromoethylindole (BEI-9) redirects NF-κB signaling induced by camptothecin and TNFα to promote cell death in colon cancer cells.

Chowdhury Rupak R Gales Dominique D Valenzuela Paloma P Miller Sonni S Yehualaeshet Teshome T Manne Upender U Francia Giulio G Samuel Temesgen T

Apoptosis : an international journal on programmed cell death 20171201 12

Chemotherapeutic regimens containing camptothecin (CPT), 5-fluorouracil, and oxaliplatin are used to treat advanced colorectal cancer. We previously reported that an indole derivative, 3-(2-bromoethyl)indole (BEI-9), inhibited the proliferation of colon cancer cells and suppressed NF-κB activation. Here, we show that a combination of BEI-9 with either CPT or tumor necrosis factor alpha (TNFα) enhances cell death. Using colorectal cancer cells, we examined the activation of NF-κB by drugs, the po ...[more]

PMID: 29116428

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Project description:BackgroundChronic alcohol consumption is more frequently associated with advanced, aggressive hepatocellular carcinoma (HCC) tumors. Alcohol adversely impacts ER/Golgi membrane trafficking and Golgi protein N-glycosylation in hepatocytes; these effects have been attributed (in part) to dysregulated adenosine diphosphate-ribosylation factor (ARF) GTPase signaling. Here, we investigated the role of the ARF GTPase guanine exchange factor PSD4 in HCC progression.MethodsR-based bioinformatics analysis was performed on publicly available array data. Modulating gene expression was accomplished via lentiviral vectors. Gene expression was analyzed using quantitative real-time PCR and immunoblotting. PSD4 promoter methylation was assessed using quantitative methylation-specific PCR. Phospho-p65(S276)/DNMT1 binding to the PSD4 promoter was analyzed via chromatin immunoprecipitation. We constructed ethanol/DEN-induced and DEN only-induced transgenic murine models of HCC.ResultsWe identified PSD4 as a hypermethylated, suppressed gene in alcohol-related HCC tumors; however, PSD4 was not dysregulated in all-cause HCC tumors. Certain HCC cell lines also displayed varying degrees of PSD4 downregulation. PSD4 overexpression or knockdown decreased and increased cell migration and invasiveness, respectively. Mechanistically, PSD4 transcription was repressed by TNF-α-induced phospho-p65(S276)'s recruitment of DNA methyltransferase 1 (DNMT1), resulting in PSD4 promoter methylation. PSD4 inhibited pro-EMT CDC42 activity, resulting in downregulation of E-cadherin and upregulation of N-cadherin and vimentin. Hepatocyte-specific PSD4 overexpression reduced ethanol/DEN-induced HCC tumor progression and EMT marker expression in vivo.ConclusionsPSD4 is a hypermethylated, suppressed gene in alcohol-related HCC tumors that negatively modulated pro-EMT CDC42 activity. Furthermore, we present a novel phospho-NF-κB p65(S276)/DNMT1-mediated promoter methylation mechanism by which TNF-α/NF-κB signaling represses PSD4 transcription in HCC cells.

Dataset Information

Bromoethylindole (BEI-9) redirects NF-?B signaling induced by camptothecin and TNF? to promote cell death in colon cancer cells.

Publications

Bromoethylindole (BEI-9) redirects NF-κB signaling induced by camptothecin and TNFα to promote cell death in colon cancer cells.

Similar Datasets

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