FBXO32 activates NF-κB through IκBα degradation in inflammatory and genotoxic stress

Meshram, Sachin N.; Paul, Debasish; Manne, Rajeshkumar; Choppara, Srinadh; Sankaran, Ganga; Agrawal, Yashika; Santra, Manas Kumar

doi:10.1016/j.biocel.2017.09.021

Cited by 16 publications

(15 citation statements)

References 31 publications

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“…Ac suppresses the inflammatory response after injury via regulation of the NF-κB signaling pathway (14,32,33). IκBα is an inhibitory protein of the NF-κB signaling pathway that normally binds to P65 resulting in the inhibition of P65 phosphorylation and its nuclear translocation (34). conversely, IκBα phosphorylation promotes its own ubiquitination and degradation, thereby eliminating the inhibitory effect on P65 (35,36).…”

Section: Discussionmentioning

confidence: 99%

Asiaticoside suppresses cell proliferation by inhibiting the NF‑κB signaling pathway in colorectal cancer

Zhou

et al. 2020

Int J Mol Med

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colorectal cancer (cRc) is one of the leading causes of cancer-associated mortality. Asiaticoside (Ac) exhibits antitumor effects; however, to the best of our knowledge, the biological function of Ac in cRc cells remains unclear. Therefore, the aim of the present study was to investigate the effect of Ac on cRc cells. In the present study, ccK-8 and colony formation assays were performed to assess the effects of AV on human cRc cell lines (HcT116, SW480 and LoVo). Mitochondrial membrane potential was examined by Jc-1 staining. cell apoptosis and cell cycle were monitored by flow cytometry, and the expression of genes was evaluated using RT-qPcR and western blot analysis. Furthermore, the biological effect of Ac in vivo was detected using a xenograft mouse model. The findings revealed that 2 µM AC suppressed the proliferation of cRc cells in a time-and dose-dependent manner, but had no adverse effects on normal human intestinal FHc cells at a range of concentrations. Ac decreased the mitochondrial membrane potential and increased the apoptosis of cRc cells in a dose-dependent manner. Furthermore, Ac induced cell cycle arrest at the G0/G1 phase. Ac attenuated IκBα phosphorylation in a dose-dependent manner, thereby preventing P65 from entering the nucleus, and resulting in inhibition of the NF-κB signaling pathway. In addition, Ac significantly reduced the expression of CDK4 and Cyclin D1 in a dose-dependent manner, significantly upregulated the activation of caspase-9 and caspase-3, and decreased the Bcl-2/Bax mRNA ratio. Furthermore, treatment with the NF-κB signaling pathway inhibitor JSH-23 significantly increased the cytotoxicity of Ac in cRc cells. Findings of the xenograft mice model experiments revealed that AC significantly inhibited colorectal tumor growth in a dose-dependent manner. Overall, Ac suppressed activation of the NF-κB signaling pathway by downregulating IκBα phosphorylation. This resulted in inhibition of cRc cell viability and an increase of cell apoptosis, which may form the basis of Ac use in the treatment of patients with cRc.

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Section: Discussionmentioning

confidence: 99%

Asiaticoside suppresses cell proliferation by inhibiting the NF‑κB signaling pathway in colorectal cancer

Zhou

et al. 2020

Int J Mol Med

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“…That finding is just in line with present results that NFκB1 was highly expressed in ovarian cancer and positively regulated by LINC00494 as its target gene. In addition, FBXO32 targets IκBα proteasome degradation in breast and human kidney transformed cells, while FBXO32 contributes the activation of NF-κB pathway in various tissues, while also exacerbating inflammation and genotoxic stress in breast cancer MCF7 cells ( 27 ). FBXO32 is activated under various stresses, making it a general marker of cellular stress responses.…”

Section: Discussionmentioning

confidence: 99%

LINC00494 Promotes Ovarian Cancer Development and Progression by Modulating NFκB1 and FBXO32

Yang

Zhang

et al. 2021

Front. Oncol.

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BackgroundOvarian cancer represents one of the most frequent gynecological cancers and is significant cause of death for women around the world. Long non-coding RNAs (lncRNAs) are recognized as critical governors of gene expression during carcinogenesis, but their effects on the occurrence and development of ovarian cancer require further investigation. In this report, we characterized LINC00494 as a novel oncogenic lncRNA in ovarian cancer.MethodsBioinformatics analysis predicted potential interactions among LINC00494, NFκB1, and FBXO32 in ovarian cancer, which were tested by dual-luciferase reporter assay, RNA pull-down, RIP, and ChIP assay. Cancer cells were transfected with relevant treated plasmids, followed by scratch and Transwell assays. The treated cells were injected into nude mice to establish a xenograft model for testing effects of LINC00494 and its target gene in vivo.ResultsLINC00494 and NFκB1 were highly expressed whereas FBXO32 had low expression in ovarian cancer cells and tissues. LINC00494 was found to bind NFκB1 and increase its activity, while NFκB1 was enriched at the FBXO32 promoter region, where it acted to reduce FBXO32 transcription. Overexpression of LINC00494 elevated NFκB1 expression and enhanced cell migration, invasion and tumorigenesis, but additional overexpression of FBXO32 interfered with the tumorgenicity of ovarian cancer cells in vitro and in vivo.ConclusionOur work demonstrated that LINC00494 promoted ovarian cancer progression by modulating FBXO32 via binding with the transcription factor NFκB1. These results provided new insight into the mechanism of ovarian cancer pathogenesis and suggested new therapeutic targets.

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“…Lentiviral shRNAs (For SDS22, shRNA 1: V2LHS_170323, shRNA 2: V3LHS_340369, and V3LHS_340373) were a kind gift from Prof. Michael R. Green, University of Massachusetts Medical School, USA. HEK-293 T cells were co-transfected with the indicated shRNAs along with packaging vectors (pPAX2 and pMD2.G) using polyethylenimine (Polyscience, USA) as reported earlier [26] .…”

Section: Methodsmentioning

confidence: 99%

“…Quantitative real time RT-PCR was performed as described previously [26] . The expression of GAPDH was used to normalize the data.…”

Section: Methodsmentioning

confidence: 99%

Protein Phosphatase 1 Regulatory Subunit SDS22 Inhibits Breast Cancer Cell Tumorigenesis by Functioning as a Negative Regulator of the AKT Signaling Pathway

et al. 2019

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Protein phosphatases play a crucial role in cell cycle progression, cell survival, cellular signaling, and genomic integrity. The protein phosphatase 1 (PP1) regulatory subunit SDS22 plays a significant role in cell cycle progression. A recent study showed that SDS22 plays a vital role in epithelial integrity and tumor suppression in Drosophila. However, its tumor suppressive activity remains obscure in the mammalian system. Here, for the first time, we show that SDS22 inhibits the growth of breast cancer cells through induction of apoptosis. SDS22 negatively regulates the AKT kinase signaling pathway through PP1. SDS22 associates predominantly with AKT and dephosphorylates the phospho Thr308 and phospho Ser473 through PP1 and hence abrogates the cell migration, invasion, and tumor growth. Thus, our study deciphers the long-standing question of how PP1 negatively regulates the AKT signaling pathway. Further, we observed a significant converse correlation in the expression levels of SDS22 and phospho form of AKT with reduced levels of SDS22 in the higher grades of cancer. Overall, our results suggest that SDS22 could be a putative tumor suppressor and replenishment of SDS22 would be an important strategy to restrict the tumor progression.

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FBXO32 activates NF-κB through IκBα degradation in inflammatory and genotoxic stress

Cited by 16 publications

References 31 publications

Asiaticoside suppresses cell proliferation by inhibiting the NF‑κB signaling pathway in colorectal cancer

Asiaticoside suppresses cell proliferation by inhibiting the NF‑κB signaling pathway in colorectal cancer

LINC00494 Promotes Ovarian Cancer Development and Progression by Modulating NFκB1 and FBXO32

Protein Phosphatase 1 Regulatory Subunit SDS22 Inhibits Breast Cancer Cell Tumorigenesis by Functioning as a Negative Regulator of the AKT Signaling Pathway

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