Tributyltin induces G2/M cell cycle arrest via NAD&lt;sup&gt;+&lt;/sup&gt;-dependent isocitrate dehydrogenase in human embryonic carcinoma cells

Asanagi, Miki; Yamada, Shigeru; Hirata, Naoya; Itagaki, Hiroshi; Kotake, Yaichiro; Sekino, Yuko; Kanda, Yasunari

doi:10.2131/jts.41.207

Cited by 13 publications

(12 citation statements)

References 33 publications

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“…Thus, arresting the cell cycle is considered a very effective method for eradicating tumor cells. The G2/M phase is an important checkpoint in the cell cycle that prevents the initiation of mitosis until DNA damaged during replication is repaired (25). The majority of the cells treated with angelicin were arrested in the G2/M phase.…”

Section: Discussionmentioning

confidence: 99%

“…To detect the apoptotic effects of angelicin on A549 cells, an Annexin V-FITC/propidium iodide (PI) apoptosis detection kit was used. In brief, A549 cells were seeded in a 6-well plate and incubated for 24 h; the cells were then treated with the DMSO control or angelicin (10,25 or 50 µmol) for 24 h. Next, the cells were collected, washed with PBS, and resuspended in 100 µl of 1X binding buffer. Annexin V-FITC/PI were added to each group, and the cells were incubated for 15 min at room temperature in the dark.…”

Section: Methodsmentioning

confidence: 99%

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Angelicin inhibits human lung carcinoma A549 cell growth and migration through regulating JNK and ERK pathways

Yao

et al. 2016

Oncology Reports

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Angelicin is a member of a well-known class of chemical photosensitizes that have anticancer proper-ties in several cancer cell lines. However, the effects and the potential underlying mechanisms of angelicin action on human lung cancer cells remain unclear. Here, we report that angelicin has an essential role in inhibiting human lung carcinoma growth and metastasis. We found that angelicin markedly induced cell apoptosis and arrested the cell cycle in vitro. Angelicin also inhibited the migration of non-small cell lung cancer (NSCLC) A549 cells in a Transwell assay in a dose-dependent manner. In addition, after angelicin treatment, the expression levels of Bax, cleaved caspase-3 and cleaved caspase-9 were increased, and Bcl-2 expression was decreased. Moreover, our results indicate that angelicin inhibits NSCLC growth not only by downregulating cyclin B1, cyclin E1 and Cdc2, which are related to the cell cycle, but also by reducing MMP2 and MMP9 and increasing E-cadherin expression levels. Furthermore, extracellular signal-regulated kinase (ERK)1/2 and c-Jun NH2-terminal protein kinase (JNK)1/2 phosphorylation increased in parallel with the angelicin treatments. The inhibition of ERK1/2 and JNK1/2 by specific inhibitors significantly abrogated angelicin-induced cell apoptosis, cell cycle arrest and migration inhibition. We established in vivo A549 cell transplant and metastasis models and found that angelicin exerted a significant inhibitory effect on A549 cell growth and lung metastasis. Overall, our results suggested that angelicin is able to inhibit NSCLC A549 cell growth and metastasis by targeting ERK and JNK signaling, which demonstrates potential for NSCLC therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Angelicin inhibits human lung carcinoma A549 cell growth and migration through regulating JNK and ERK pathways

Yao

et al. 2016

Oncology Reports

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“…TBT at 50 nM has the ability to bind to PPARγ with a higher affinity than that of the intrinsic ligands, and these genomic transcriptional activations have been reported to mediate neurodevelopmental defects 5 . To investigate the molecular mechanisms by which TBT inhibits ectodermal induction, we examined the effect of the PPARγ agonist rosiglitazone (RGZ), which had been confirmed in our previous report, as having agonistic effects on PPARγ 10 . We found that RGZ did not reduce OTX2 expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to the genomic effects, we previously found the non-genomic action of TBT. TBT reduced intracellular ATP levels by targeting glycolysis and mitochondrial systems, and inhibited the growth of human embryonic carcinoma NT2/D1 cells 7 – 10 . We also found that TBT induced the growth inhibition of human induced pluripotent stem cells (iPSCs) through mitochondrial dysfunction, such as decreased ATP levels, depolarization of mitochondrial membrane potential (MMP) and mitochondrial fragmentation, via the degradation of mitochondrial fusion factor, mitofusin1 (Mfn1) 11 .…”

Section: Introductionmentioning

confidence: 99%

Tributyltin Inhibits Neural Induction of Human Induced Pluripotent Stem Cells

Yamada

Kubo

Yamazaki

et al. 2018

Sci Rep

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Tributyltin (TBT), one of the organotin compounds, is a well-known environmental pollutant. In our recent study, we reported that TBT induces mitochondrial dysfunction, in human-induced pluripotent stem cells (iPSCs) through the degradation of mitofusin1 (Mfn1), which is a mitochondrial fusion factor. However, the effect of TBT toxicity on the developmental process of iPSCs was not clear. The present study examined the effect of TBT on the differentiation of iPSCs into the ectodermal, mesodermal, and endodermal germ layers. We found that exposure to nanomolar concentration of TBT (50 nM) selectively inhibited the induction of iPSCs into the ectoderm, which is the first step in neurogenesis. We further assessed the effect of TBT on neural differentiation and found that it reduced the expression of several neural differentiation marker genes, which were also downregulated by Mfn1 knockdown in iPSCs. Taken together, these results indicate that TBT induces developmental neurotoxicity via Mfn1-mediated mitochondrial dysfunction in iPSCs.

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“…RT-PCR was performed as previously reported (Asanagi et al, 2016;Hirata et al, 2017). Briefly, total RNA was isolated from iPSCs using TRIzol reagent (Thermo Fisher Scientific).…”

Section: Real-time Polymerase Chain Reaction (Pcr)mentioning

confidence: 99%

5-Fluorouracil inhibits neural differentiation via Mfn1/2 reduction in human induced pluripotent stem cells

2018

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-5-fluorouracil (5-FU) has been widely used for the treatment of tumors. Regardless of its widespread use as an anti-cancer drug, 5-FU therapy can cause several side effects, including developmental toxicity and neurotoxicity. However, the potential action of 5-FU at the early fetal stage has not yet been completely elucidated. In the present study, we investigated the effect of 5-FU exposure on neural induction, using human induced pluripotent stem cells (iPSCs) as a model of human fetal stage. 5-FU exposure reduced the expression of several neural differentiation marker genes, such as OTX2, in iPSCs. Since the neural differentiation process requires ATP as a source of energy, we next examined intracellular ATP content using iPSCs. We found that 5-FU decreased intracellular ATP levels in iPSCs. We further focused on the effects of 5-FU on mitochondrial dynamics, which plays a role of ATP production. We found that 5-FU induced mitochondrial fragmentation and reduced the level of mitochondrial fusion proteins, mitofusin 1 and 2 (Mfn1/2). Double knockdown of Mfn1/2 genes in iPSCs downregulated the gene expression of OTX2, suggesting that Mfn mediates neural differentiation in iPSCs. Taken together, these results indicate that 5-FU has a neurotoxicity via Mfn-mediated mitochondria dynamics in iPSCs. Thus, mitochondrial dysfunction in iPSCs could be used as a possible marker for cytotoxic effects of drugs.

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Tributyltin induces G2/M cell cycle arrest via NAD<sup>+</sup>-dependent isocitrate dehydrogenase in human embryonic carcinoma cells

Cited by 13 publications

References 33 publications

Angelicin inhibits human lung carcinoma A549 cell growth and migration through regulating JNK and ERK pathways

Angelicin inhibits human lung carcinoma A549 cell growth and migration through regulating JNK and ERK pathways

Tributyltin Inhibits Neural Induction of Human Induced Pluripotent Stem Cells

5-Fluorouracil inhibits neural differentiation via Mfn1/2 reduction in human induced pluripotent stem cells

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