Distinct B subunits of <scp>PP</scp>2A regulate the <scp>NF</scp>‐κB signalling pathway through dephosphorylation of <scp>IKK</scp>β, IκBα and RelA

Tsuchiya, Y.; Osaki, Keiko; Kanamoto, Mayu; Nakao, Yoshio; Takahashi, Ena; Higuchi, Toru; Kamata, Hideaki

doi:10.1002/1873-3468.12912

Cited by 33 publications

(23 citation statements)

References 45 publications

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“…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 ). Once P65 enters the nucleus, it triggers a series of gene expressions such as Bcl-2 and CDK4 ( 37 ).…”

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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“…PP2A may deactivate IKKα by dephosphorylation of its active site, while IKKα is involved in the stimulation of the NF-κB pathway ( 25 ). Therefore, the activities of genes involved in the NF-κB signaling pathway in QBC939 cells was determined.…”

Section: Resultsmentioning

confidence: 99%

Role of cantharidin in the activation of IKKα/IκBα/NF‑κB pathway by inhibiting PP2A activity in cholangiocarcinoma cell lines

Zhou

Wang

et al. 2018

Mol Med Report

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Cantharidin (CAN), a potent inhibitor of serine/threonine-protein phosphatase 2A (PP2A), is widely used in clinical practice, particularly in the treatment of advanced cancer due to its specific action on these types of cancer. In the present study, the inhibitory effect of CAN was examined in two cholangiocarcinoma cell lines (QBC939 and Hucc-t1). Following treatment with CAN, cell viability was effectively reduced in QBC939 and Hucc-t1 cells and normal human intrahepatic biliary epithelial cells. However, a slight increase in reactive oxygen species levels in QBC939 cells treated with CAN was observed post-treatment. CAN significantly inhibited cell migration and invasion in a dose-dependent manner. Western blot analysis demonstrated that the nuclear factor-κB (NF-κB) pathway was stimulated by CAN, which was confirmed by the upregulated phosphorylation levels of inhibitor of NF-κB kinase subunit α (IKKα) and NF-κB inhibitor α (IκBα) in cells, and an increased NF-κB p65 subunit level in the nucleus. The expression levels of 72 kDa type IV collagenase (MMP2) and matrix metalloproteinase 9 (MMP9) were downregulated by CAN. Notably, there was a negative association between MMP2 and MMP9 expression levels, and NF-κB p65, although NF-κB p65 regulates the expression of MMP2 and MMP9 and has a positive association with these proteins in various types of cancer. Notably, it was observed that CAN exerted specific inhibition on PP2A activity and thereby resulted in the activation of the IKKα/IκBα/NF-κB pathway. Therefore, CAN-induced cell inhibition maybe partially dependent on the activation of the IKKα/IκBα/NF-κB pathway. In conclusion, it was demonstrated that CAN selectively and effectively inhibited cholangiocarcinoma cell migration and invasion. The present study may provide a novel insight into the use of CAN as a therapeutic candidate in the treatment of cholangiocarcinoma.

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“…PP2A is also involved in multiple key intercellular signaling pathways, including but not limited to MAPK, AKT, NF-kB, and mTOR pathways (38)(39)(40)(41), depending on the cell type and biological response. IL-2 contributes to T cell function mainly through two signaling pathways associated with the IL-2R/ JAK1/3-STAT5 and mTORC1 pathways (42).…”

Section: Discussionmentioning

confidence: 99%

CD25 and Protein Phosphatase 2A Cooperate to Enhance IL-2R Signaling in Human Regulatory T Cells

Ding

Tsokos

et al. 2019

The Journal of Immunology

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Low-dose IL-2 therapy is a direct approach to boost regulatory T cells (Tregs) and promote immune tolerance in autoimmune patients. However, the mechanisms responsible for selective response of Tregs to low-dose IL-2 is not fully understood. In this study we directly assessed the contribution of CD25 and protein phosphatase 2A (PP2A) in promoting IL-2R signaling in Tregs. IL-2–induced tyrosine phosphorylation of STAT5 (pSTAT5) was proportional to CD25 levels on human CD4+ T cells and YT human NK cell line, directly demonstrating that CD25 promotes IL-2R signaling. Overexpression of the PP2A catalytic subunit (PP2Ac) by lentiviral transduction in human Tregs increased the level of IL-2R subunits and promoted tyrosine phosphorylation of Jak3 and STAT5. Interestingly, increased expression of CD25 only partially accounted for this enhanced activation of pSTAT5, indicating that PP2A promotes IL-2R signaling through multiple mechanisms. Consistent with these findings, knockdown of PP2Ac in human Tregs and impaired PP2Ac activity in mouse Tregs significantly reduced IL-2–dependent STAT5 activation. In contrast, overexpression or knockdown of PP2Ac in human T effector cells did not affect IL-2–dependent pSTAT5 activation. Overexpression of PP2Ac in human Tregs also increased the expressions of proteins related to survival, activation, and immunosuppressive function, and upregulated several IL-2–regulated genes. Collectively, these findings suggest that CD25 and PP2A cooperatively enhance the responsiveness of Tregs to IL-2, which provide potential therapeutic targets for low-dose IL-2 therapy.

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Distinct B subunits of PP2A regulate the NF‐κB signalling pathway through dephosphorylation of IKKβ, IκBα and RelA

Cited by 33 publications

References 45 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

Role of cantharidin in the activation of IKKα/IκBα/NF‑κB pathway by inhibiting PP2A activity in cholangiocarcinoma cell lines

CD25 and Protein Phosphatase 2A Cooperate to Enhance IL-2R Signaling in Human Regulatory T Cells

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