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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:BackgroundThe linear long non-coding RNA P14AS has previously been reported to be dysregulated in colon cancer, but the mechanistic role that P14AS plays in colon cancer progression has yet to be clarified. Accordingly, this study was developed to explore the regulatory functions of ANRIL linear transcript-P14AS in cancer.MethodsThe expression of P14AS, ANRIL, miR-23a-5p and their target genes were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell supernatants of IL6 and IL8 were measured by Enzyme linked immunosorbent (ELISA) assay. Dual-luciferase reporter assays, RNA immunoprecipitation, or pull-down assays were used to confirm the target association between miR-23a-5p and P14AS or UBE2D3. Cell proliferation and chemosensitivity of NF-κB inhibitor BAY 11-7085 were evaluated by cell counting kit 8 (CCK8).ResultsWhen P14AS was overexpressed in colon cancer cell lines, enhanced TNF-NF-κB signaling pathway activity was observed together with increases in IL6 and IL8 expression. The Pita, miRanda, and RNA hybrid databases revealed the ability of miR-23a-5p to interact with P14AS, while UBE2D3 was further identified as a miR-23a-5p target gene. The results of dual-luciferase reporter, RNA pull-down, and RNA immunoprecipitation experiments confirmed these direct interactions among P14AS/miR-23a-5p/UBE2D3. The degradation of IκBa mediated by UBE2D3 may contribute to enhanced NF-κB signaling in these cells. Moreover, the beneficial impact of P14AS on colon cancer cell growth was eliminated when cells were treated with miR-23a-5p inhibitors or UBE2D3 was silenced. As such, these findings strongly supported a role for the UBE2D3/IκBa/NF-κB signaling axis as a mediator of the ability of P14AS to promote colon cancer progression.ConclusionsThese data suggested a mechanism through which the linear ANRIL transcript P14AS can promote inflammation and colon cancer progression through the sequestration of miR-23a-5p and the modulation of NF-κB signaling activity, thus highlighting P14AS as a promising target for therapeutic intervention efforts.

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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