Alzheimer's disease (AD) is the most common cause of dementia. The neuropathological features of AD include amyloid-β (Aβ) deposition and hyperphosphorylated tau accumulation. Although several ...clinical trials have been conducted to identify a cure for AD, no effective drug or treatment has been identified thus far. Recently, the potential use of non-pharmacological interventions to prevent or treat AD has gained attention. Low-dose ionizing radiation (LDIR) is a non-pharmacological intervention which is currently being evaluated in clinical trials for AD patients. However, the mechanisms underlying the therapeutic effects of LDIR therapy have not yet been established. In this study, we examined the effect of LDIR on Aβ accumulation and Aβ-mediated pathology. To investigate the short-term effects of low-moderate dose ionizing radiation (LMDIR), a total of 9 Gy (1.8 Gy per fraction for five times) were radiated to 4-month-old 5XFAD mice, an Aβ-overexpressing transgenic mouse model of AD, and then sacrificed at 4 days after last exposure to LMDIR. Comparing sham-exposed and LMDIR-exposed 5XFAD mice indicated that short-term exposure to LMDIR did not affect Aβ accumulation in the brain, but significantly ameliorated synaptic degeneration, neuronal loss, and neuroinflammation in the hippocampal formation and cerebral cortex. In addition, a direct neuroprotective effect was confirmed in SH-SY5Y neuronal cells treated with Aβ
(2 μM) after single irradiation (1 Gy). In BV-2 microglial cells exposed to Aβ and/or LMDIR, LMDIR therapy significantly inhibited the production of pro-inflammatory molecules and activation of the nuclear factor-kappa B (NF-κB) pathway. These results indicate that LMDIR directly ameliorated neurodegeneration and neuroinflammation in vivo and in vitro. Collectively, our findings suggest that the therapeutic benefits of LMDIR in AD may be mediated by its neuroprotective and anti-inflammatory effects.
T-LAK cell originated protein kinase (TOPK) has been shown to regulate proliferation, invasion or migration of various cancer cells. However, the role of TOPK in follicle environments remains ...unknown. Here we reveal that TOPK inhibits TNF-α-induced human granulosa COV434 cell apoptosis. The expression of TOPK were increased in COV434 cells in response to TNF-α. TOPK inhibition also decreased TNF-α-induced SIRT1 expression but promoted TNF-α-induced p53 acetylation and expression of PUMA or NOXA. Accordingly, TOPK inhibition attenuated TNF-α-mediated SIRT1 transcriptional activity. In addition, SIRT1 inhibition augmented acetylation of p53 or expression of PUMA and NOXA in response to TNF-α, leading to COV434 cell apoptosis. We conclude that TOPK suppresses TNF-α-induced COV434 granulosa cell apoptosis via regulation of p53/SIRT1 axis, suggesting a potential role of TOPK in regulation of ovarian follicular development.
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•TNF-α induces apoptosis of human granulosa cell line, COV434.•TOPK inhibition downregulates SIRT1 expression in TNF-α response.•Suppression of SIRT1 activity enhances TNF-α-induced p53 activity to increase expression of PUMA or NOXA.•SIRT1 inhibition enhances granulosa cell apoptosis in response to TNF-α.
Hypoxia has been suggested to induce epithelial-mesenchymal transition (EMT) in various cancer types via the transcription factor hypoxia-inducible factor-1 alpha (HIF-1α). Here, we demonstrated that ...TOPK upregulates EMT and the invasion of H460 nonsmall-cell lung cancer cells through the induction of the HIF-1α/Snail axis and hypoxic signaling. The expression of endogenous TOPK, phosphorylated TOPK, HIF-1α and Snail was significantly increased upon hypoxia exposure, but TOPK depletion markedly abrogated the induced mRNA and protein levels of HIF-1α and Snail. Interestingly, TOPK knockdown restored the hypoxia-induced suppression of E-cadherin and diminished hypoxia-induced N-cadherin expression. In addition, Snail depletion suppressed hypoxia-induced N-cadherin expression, which was attenuated by TOPK knockdown. Moreover, knockdown of Snail decreased hypoxia-induced nonsmall-cell lung cancer cell migration and invasion, which were suppressed by TOPK depletion. In summary, we conclude that TOPK positively regulates HIF-1α expression through hypoxia signaling and thereby promotes Snail expression, leading to EMT and the invasion of nonsmall-cell lung cancer cells. These findings suggest that TOPK plays a critical role as a novel mediator of hypoxia signaling that regulates nonsmall-cell lung cancer development.
•TOPK upregulates HIF-1α and Snail in hypoxia signaling to promote EMT and invasion of nonsmall-cell lung cancer cells.•Expression of endogenous HIF-1α or Snail induced by hypoxia was abolished by TOPK knockdown.•Ablation of TOPK recovered hypoxia-suppressed E-cadherin and diminished hypoxia-induced N-cadherin.•Hypoxia-induced N-cadherin expression, which was suppressed by TOPK knockdown was mitigated by Snail depletion.•Snail knockdown decreased hypoxia-induced non-small-cell lung cancer cell migration and invasion repressed by TOPK depletion.
PDZ‐binding kinase (PBK) has previously been shown to mediate chemoresistance of cancer cells to anticancer drugs. However, it remains unclear how PBK regulates paclitaxel‐induced cancer cell death. ...Here, we demonstrate that PBK hinders paclitaxel‐mediated autophagic cell death in H460 non‐small‐cell lung cancer cells. PBK knockdown increased apoptosis, autophagy, p53 level, and LC3 puncta upon paclitaxel treatment. Moreover, p53 expression facilitated an increase in the LC3‐II/LC3‐I ratio in response to paclitaxel, and PBK knockdown augmented paclitaxel‐mediated p53 transcriptional activity. Meanwhile, paclitaxel induced PBK‐mediated p53 nuclear export and its subsequent ubiquitination in control cells, but not in PBK knockdown cells. We conclude that PBK hampers paclitaxel‐induced autophagic cell death by suppressing p53, suggesting a potential role of PBK in p53‐mediated H460 cell death.
When PDZ‐binding kinase (PBK) is present (B), PBK interacts with p53 in the nucleus and then translocates to the cytoplasm upon paclitaxel treatment, leading to Mdm2‐mediated p53 ubiquitination and subsequent degradation, which induces a decrease in p53‐mediated apoptosis or autophagy in H460 non‐small‐cell lung cancer cells. In contrast, p53‐mediated apoptosis and autophagy are markedly promoted in the absence of PBK (A).
TOPK has been suggested to contribute to invasion of lung, prostate, gastric, pancreatic or breast cancer cells. However, how TOPK mediates TGF-β1/Smad signaling leading to epithelial-mesenchymal ...transition (EMT) and invasion of breast cancer cells remains unknown. Here we report that TOPK upregulates T-box transcription factor TBX3 to enhance TGF-β1-induced EMT and invasion of MDA-MB-231 breast cancer cells. Expression of endogenous TOPK was promoted by TGF-β1 treatment of MDA-MB-231 cells time-dependently. In addition, knockdown of TOPK attenuated TGF-β1-induced phosphorylation or transcriptional activity of Smad3. Meanwhile, levels of both mRNA and protein of TBX3 induced by TGF-β1 were abolished by TOPK depletion. Also, knockdown of TBX3 inhibited TGF-β1 induction of EMT-related genes Snail, Slug or Fibronectin. Furthermore, ablation of TOPK or TBX3 suppressed TGF-β1-induced MDA-MB-231 cell invasion. Collectively, we conclude that TOPK positively regulates TBX3 in TGF-β1/Smad signaling pathway, thereby enhancing EMT and invasion of breast cancer cells, implying a mechanistic role of TOPK in TGF-β1/Smad signaling.
•TOPK upregulates TBX3 leading to promotion of TGF-β1-induced EMT and invasion of breast cancer cells.•Expression of endogenous TOPK was induced by TGF-b1 treatment time-dependently.•Depletion of TOPK decreased TGF-b1-induced phosphorylation or transcriptional activity of Smad3.•TGF-b1-induced TBX3 was abolished by TOPK knockdown.•TBX3 knockdown inhibited TGF-b1 induction of Snail, Slug or Fibronectin.•Ablation of TOPK or TBX3 blocked TGF-b1-induced breast cancer cell invasion.
The phlorotannin compounds, dieckol and phlorofucofuroeckol (PFF), extracted from
Ecklonia cava
, have been suggested to exhibit anti-inflammatory, anti-adipogenic or anti-tumorigenic activity. ...However, role of dieckol or PFF in LPS/TLR-4 signaling that regulates cancer development still remains to be determined. Here we report that dieckol or PFF blocked lipopolysaccharide (LPS)-induced migration and invasion of human breast cancer MCF-7 or MDA-MB-231 cells by about 50% (
p
< 0.0001) or 60% (
p
= 0.0001), respectively. Also, PFF as well as dieckol markedly attenuated both of LPS-induced Toll-like receptor4 (TLR-4) expression and NF-κB promoter-driven transcriptional activity, which are essential for the migration and invasion. Moreover, LPS induction of NF-κB-dependent gene, matrix metalloproteinase9 (MMP-9) was markedly decreased about 2.6 or 2.5 fold by dieckol and PFF, respectively. In addition, LPS-induced MMP-2 gene expression was reduced about 1.7 or 2.1 fold by dieckol and PFF, respectively. Significantly, each inhibitor of MMP-9 or NF-κB notably reduced invasion of MDA-MB-231 cells in response to LPS by about 70% (
p
= 0.0115) or 40% (
p
< 0.0001), respectively. Collectively, these findings demonstrate that both of dieckol and PFF functions as a critical inhibitor of LPS-induced breast cancer cell invasion through downregulation of TLR-4-NF-κB-MMP-9 signaling axis, suggesting a potential role of the phlorotannins in inflammation-mediated breast cancer development.
TGF-β1 is known to induce epithelial-mesenchymal transition (EMT), which is a prerequisite for cancer cell invasion. Here we reveal that TOPK upregulates EMT and invasion of human breast cancer ...MDA-MB-231 or Hs578T cells via NF-κB-dependent Snail/Slug in TGF-β1 signaling. Endogenous TOPK expression was significantly increased in response to TGF-β1 and TOPK knockdown mitigated TGF-β1-induced breast cancer cell invasion. Interestingly, TOPK knockdown restored TGF-β1 suppression of E-cadherin expression and markedly reduced N-cadherin induced by TGF-β1. Also, NF-κB activity or expression of EMT markers Snail and Slug induced by TGF-β1 was decreased by TOPK knockdown. Meanwhile, knockdown of Snail or TOPK attenuated TGF-β1-induced breast cancer cell invasion. Taken, we conclude that TOPK mediates TGF-β1-induced EMT and invasion in breast cancer cells via NF-κB/Snail signaling, suggesting novel role of TOPK as therapeutic target in TGF-β1-mediated breast cancer development.
•TGF-β1-induced TOPK upregulates EMT and invasion of breast cancer cells via NF-kB-dependent Snail/Slug.•TOPK knockdown restored TGF-b1-mediated E-cadherin suppression and alleviated TGF-b1-induced N-cadherin.•TGF-b1-induced NF-kB activity or expression of Snail and Slug was decreased by TOPK depletion.•Knockdown of TOPK or Snail reduced TGF-b1-induced breast cancer cell invasion.
Tau, a microtubule-associated protein expressed in mature neurons, interacts with tubulin to promote the assembly and stabilization of microtubules. However, abnormally hyperphosphorylated tau ...dissociates from microtubules and self-aggregates. Tau aggregates, including paired helical filaments and neurofibrillary tangles, promote neuronal dysfunction and death and are the defining neuropathological feature of tauopathies. Therefore, suppressing tau aggregation or stimulating the dissociation of tau aggregates has been proposed as an effective strategy for treating neurodegenerative diseases associated with tau pathology such as Alzheimer’s disease (AD) and frontotemporal dementia. Interestingly, ginsenosides extracted from Panax ginseng reduced the hippocampal and cortical expression of phosphorylated tau in a rat model of AD. However, no studies have been conducted into the effect of red ginseng (RG) and its components on tau pathology. Here, we evaluated the effect of Korean red ginseng extract (KRGE) and its components on the aggregation and disassociation of tau. Using the thioflavin T assay, we monitored the change in fluorescence produced by the aggregation or disassociation of tau K18, an aggregation-prone fragment of tau441 containing the microtubule-binding domain. Our analysis revealed that KRGE not only inhibited tau aggregation but also promoted the dissociation of tau aggregates. In addition, the KRGE fractions, such as saponin, nonsaponin, and nonsaponin fraction with rich polysaccharide, also inhibited tau aggregation and promoted the dissociation of tau aggregates. Our observations suggest that RG could be a potential therapeutic agent for the treatment of neurodegenerative diseases associated with tauopathy.
Cyclin D1 is immediately down-regulated in response to reactive oxygen species (ROS) and implicated in the induction of cell cycle arrest in G2 phase by an unknown mechanism. Either treatment with a ...protease inhibitor alone or expression of protease-resistant cyclin D1 T286A resulted in only a partial relief from the ROS-induced cell cycle arrest, indicating the presence of an additional control mechanism.
Cells were exposed to hydrogen peroxide (H2O2), and analyzed to assess the changes in cyclin D1 level and its effects on cell cycle processing by kinase assay, de novo synthesis, gene silencing, and polysomal analysis, etc.
Exposure of cells to excessive H2O2 induced ubiquitin-dependent proteasomal degradation of cyclin D1, which was subsequently followed by translational repression. This dual control mechanism was found to contribute to the induction of cell cycle arrest in G2 phase under oxidative stress. Silencing of an eIF2α kinase PERK significantly retarded cyclin D1 depletion, and contributed largely to rescuing cells from G2 arrest. Also the cyclin D1 level was found to be correlated with Chk1 activity.
In addition to an immediate removal of the pre-existing cyclin D1 under oxidative stress, the following translational repression appear to be required for ensuring full depletion of cyclin D1 and cell cycle arrest. Oxidative stress-induced cyclin D1 depletion is linked to the regulation of G2/M transit via the Chk1–Cdc2 DNA damage checkpoint pathway.
The control of cyclin D1 is a gate keeping program to protect cells from severe oxidative damages.
•Cyclin D1 depletion is implicated in ROS-induced cell cycle arrest.•Exposure of cells to ROS immediately induced proteolysis of cyclin D1.•Exposure to excessive ROS activated Perk-mediated translation repression.•Cyclin D1 is linked to the regulation of G2/M transit via the Chk1 pathway.
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