Selenite induces cell cycle arrest and apoptosis through ROS-dependent inhibition of the AKT/mTOR pathway in thyroid cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE168843 | GEO | 2021/03/13
REPOSITORIES: GEO
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Project description:Selenite induces cell cycle arrest and apoptosis through ROS-dependent inhibition of the AKT/mTOR pathway in thyroid cancer
| PRJNA714134 | ENA
Project description:Thyroid cancer is the most common endocrine malignancy, and its incidence has increased in the past decades. Selenium has been shown to have therapeutic effects against several tumors. However, its role in thyroid cancer and its underlying molecular mechanism remains to be explored. In the present study, we demonstrated that sodium selenite significantly decreased cell viability and induced G0/G1 cell cycle arrest and apoptosis in thyroid cancer cells in a dose-dependent manner. Transcriptomics revealed that sodium selenite induced intracellular reactive oxygen species (ROS) by promoting oxidative phosphorylation. Increased intracellular ROS levels inhibited the AKT/mTOR signaling pathway and upregulated EIF4EBP3. Intracellular ROS inhibition by N-acetylcysteine (NAC) ameliorated the cellular effects of sodium selenite. The in vitro findings were reproduced in xenograft thyroid tumor models. Our data demonstrated that sodium selenite exhibits strong anticancer effects against thyroid cancer cells, which involved ROS-mediated inhibition of the AKT/mTOR pathway. This suggests that sodium selenite may serve as a therapeutic option for advanced thyroid cancer.
| S-EPMC8176115 | biostudies-literature
Project description:The bacterium Pseudomonas putida KT2440 has the ability to reduce selenite forming nanoparticles of elemental selenium. This is the transcriptome of the organism when cultured in the presence of selenite.
2022-10-01 | GSE214391 | GEO
Project description:Selenium (Se) is an essential trace element known for its significant role in maintaining human health and mitigating disease progression. Selenium and its compounds exhibit high selective cytotoxicity against tumor cells. However, their anti-cervical cancer (CC) effects and underlying mechanisms have not been fully explored. This study found that sodium selenite (SS) inhibits the viability of HeLa and SiHa cells in a dose- and time-dependent manner. Intraperitoneal injection of 3 and 6 mg/kg SS for 14 days in female nude mice significantly inhibited the growth of HeLa cell xenografts without evident hepatotoxicity or nephrotoxicity. RNA sequencing results indicated that the AMP-activated protein kinase (AMPK), Forkhead box protein O (FOXO), and apoptosis signaling pathways are key regulatory pathways in SS's anti-CC effects, and SS's inhibition of HeLa cell proliferation may be related to autophagy and ROS-induced apoptosis. Further research has revealed that SS induces cell autophagy and apoptosis through the AMPK/mTOR/FOXO3a pathway, characterized by the upregulation of p-AMPK/AMPK, FOXO3a, LC3-II, cleaved-caspase3, and cleaved-PARP and the downregulation of p-mTOR/mTOR and p62. Additionally, SS impaired mitochondrial function, including decreased mitochondrial membrane potential, mitochondrial Ca2+ overload, and accumulation of mitochondrial reactive oxygen species (mtROS). Pretreatment with Mitoquinone mesylate (Mito Q) and compound C partially reversed SS-induced apoptosis, autophagy, and proliferation inhibition. Pretreatment with 3-methyladenine (3-MA) enhances SS-induced apoptosis and proliferation inhibition in HeLa cells but reverses these effects in SiHa cells. In summary, SS induces apoptosis, autophagy, and proliferation inhibition in HeLa and SiHa cells through the activation of the AMPK/mTOR/FOXO3a signaling pathway via mtROS. Autophagy activation may be a major risk factor for SS-induced apoptosis in SiHa cells but can protect HeLa cells from SS-induced apoptosis. These findings provide new evidence for understanding the molecular mechanisms underlying SS in potential new drug development for CC.
| S-EPMC11352036 | biostudies-literature
Project description:The yeast S. cerevisiae does not require selenium for growth, so it is an excellent model to investigate the toxicity of this element without interference from its requirement as growth factor as occurs in animal cells. Exposure to selenite interferes with the yeast iron metabolism. Aft2 is a transcription factor related (with Aft1) to maintenance of iron homeostasis. We have found that aft2 cells are highly sensitive to selenite (a common environmental source for selenium). In these experiments we investigate the transcriptional response to a sub-lethal dose of selenite in wild type and aft2 cells. Our results show that the aft2 mutation strongly potentiates the transcriptional response to selenite, showing induction of many genes related to the responses to oxidative stress and DNA damage.
2015-12-31 | GSE70835 | GEO
Project description:Apatinib, an inhibitor of vascular endothelial growth factor receptor-2, has been shown to promote anti-cancer action across a wide range of malignancies, including gastric, lung, and breast cancers. Our previous study showed that apatinib increases apoptosis in anaplastic thyroid carcinoma (ATC), but the direct functional mechanism of tumor lethality mediated by apatinib is still unknown. In this study, we demonstrated that apatinib induced both autophagy and apoptosis in human ATC cells through downregulation of p-AKT and p-mTOR signals via the AKT/mTOR pathway. Moreover, inhibition of apatinib-induced autophagy increased apatinib-induced apoptosis in ATC cells, and additional tumor suppression was critically produced by the combination of apatinib and the autophagy inhibitor chloroquine in vivo and in vitro. These findings showed that both autophagy and AKT/mTOR signals were engaged in ATC cell death evoked by apatinib. ATC patients might benefit from the new anti-cancer drug, and molecular targeted treatment in combination with autophagy inhibitors shows promise as a treatment improvement.
| S-EPMC6177436 | biostudies-literature
Project description:Thyroid cancer (TC) is the most common endocrine malignancy, and its global incidence has steadily increased over the past 15 years. TC is broadly divided into well-differentiated, poorly differentiated, and undifferentiated types, depending on the histological and clinical parameters. Thus far, there are no effective treatments for undifferentiated thyroid cancers or advanced and recurrent cancer. Therefore, the development of an effective therapeutic is urgently needed for such patients. Piperlongumine (PL) is a naturally occurring small molecule derived from long pepper; it is selectively toxic to cancer cells by generating reactive oxygen species (ROS). In this study, we demonstrate the potential anticancer activity of PL in four TC cell lines. For this purpose, we cultured TC cell lines and analyzed the following parameters: Cell viability, colony formation, cell cycle, apoptosis, and cellular ROS induction. PL modulated the cell cycle, induced apoptosis, and suppressed tumorigenesis in TC cell lines in a dose- and time-dependent manner through ROS induction. Meanwhile, an intrinsic caspase-dependent apoptosis pathway was observed in the TC cells under PL treatment. The activation of Erk and the suppression of the Akt/mTOR pathways through ROS induction were seen in cells treated with PL. PL-mediated apoptosis in TC cells was through the ROS-Akt pathway. Finally, the anticancer effect and safety of PL were also demonstrated in vivo. Our findings indicate that PL exhibits antitumor activity and has the potential for use as a chemotherapeutic agent against TC. This is the first study to show the sensitivity of TC cell lines to PL.
| S-EPMC8428232 | biostudies-literature
Project description:BackgroundSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection-induced inflammatory responses are largely responsible for the death of novel coronavirus disease 2019 (COVID-19) patients. However, the mechanism by which SARS-CoV-2 triggers inflammatory responses remains unclear. Here, we aimed to explore the regulatory role of SARS-CoV-2 spike protein in infected cells and attempted to elucidate the molecular mechanism of SARS-CoV-2-induced inflammation.MethodsSARS-CoV-2 spike pseudovirions (SCV-2-S) were generated using the spike-expressing virus packaging system. Western blot, mCherry-GFP-LC3 labeling, immunofluorescence, and RNA-seq were performed to examine the regulatory mechanism of SCV-2-S in autophagic response. The effects of SCV-2-S on apoptosis were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), Western blot, and flow cytometry analysis. Enzyme-linked immunosorbent assay (ELISA) was carried out to examine the mechanism of SCV-2-S in inflammatory responses.ResultsAngiotensin-converting enzyme 2 (ACE2)-mediated SCV-2-S infection induced autophagy and apoptosis in human bronchial epithelial and microvascular endothelial cells. Mechanistically, SCV-2-S inhibited the PI3K/AKT/mTOR pathway by upregulating intracellular reactive oxygen species (ROS) levels, thus promoting the autophagic response. Ultimately, SCV-2-S-induced autophagy triggered inflammatory responses and apoptosis in infected cells. These findings not only improve our understanding of the mechanism underlying SARS-CoV-2 infection-induced pathogenic inflammation but also have important implications for developing anti-inflammatory therapies, such as ROS and autophagy inhibitors, for COVID-19 patients.
| S-EPMC8390448 | biostudies-literature
Project description:BackgroundCelastrol, a triterpene compound derived from the traditional Chinese medicine Tripterygium wilfordii, has been reported to possess potential antitumor activity towards various malignancies. However, the effect of celastrol on glioma cells and the underlying molecular mechanisms remain elusive.MethodsGlioma cells, including the U251, U87-MG and C6 cell lines and an animal model were used. The effects of celastrol on cells were evaluated by flow cytometry, confocal microscopy, reactive oxygen species production assay and immunoblotting after treatment of celastrol. Fisher's exact test, a one-way ANOVA and the Mann-Whitney U-test were used to compare differences between groups. All data were analyzed using SPSS version 21.0 software.ResultsHere, we found that exposure to celastrol induced G2/M phase arrest and apoptosis. Celastrol increased the formation of autophagosomes, accumulation of LC3B and the expression of p62 protein. Celastrol-treated glioma cells exhibited decreased cell viability after the use of autophagy inhibitors. Additionally, autophagy and apoptosis caused by celastrol in glioma cells inhibited each other. Furthermore, celastrol induced JNK activation and ROS production and inhibited the activities of Akt and mTOR kinases. JNK and ROS inhibitors significantly attenuated celastrol-trigged apoptosis and autophagy, while Akt and mTOR inhibitors had opposite effects.ConclusionsIn conclusion, our study revealed that celastrol caused G2/M phase arrest and trigged apoptosis and autophagy by activating ROS/JNK signaling and blocking the Akt/mTOR signaling pathway.
| S-EPMC6500040 | biostudies-literature
Project description:Xihuang pill (XHP), a traditional Chinese herbal formula, has long been used as an effective agent against multiple tumors. The aim of this study is to evaluate the effects of XHP on the growth inhibition and apoptosis in glioblastoma U-87 MG cells. Gas chromatography-mass spectrometry (GC-MS) was performed for constituent analysis of XHP. Cell viability, cell cycle arrest, generation of reactive oxygen species (ROS), and apoptosis were measured by CCK-8 assay, PI/RNase staining, DCFH-DA assay, TUNEL assay, Annexin V-FITC/PI double staining, and JC-1 assay, respectively. The role of XHP in the regulation of Akt/mTOR/FOXO1 interaction was clarified by using Western Blotting (WB), immunofluorescence (IF), pharmacological inhibitor or antioxidant, and siRNA silencing. The results suggested that XHP could inhibit U-87 MG cells growth and arrest cells in S-phase cell cycle significantly and that the generation of ROS, collapse of mitochondrial membrane potential, enhancement of Bax/Bcl-xL ratio, and reduction of the precursor forms of caspase-9 and caspase-3 caused by XHP prompted that a ROS-mediated mitochondria-dependent apoptosis was possibly involved. Furthermore, XHP affected the Akt/mTOR/FOXO1 pathway via inhibiting the phosphorylation of Akt, mTOR, and FOXO1 and increasing both prototype and nuclear translocation of FOXO1. Inhibition of Akt, mTOR, and FOXO1 by specific inhibitors or siRNA could interpose the apoptotic induction. In conclusion, we demonstrate for the first time that XHP may regulate glioblastoma U-87 MG cell apoptosis via ROS-mediated Akt/mTOR/FOXO1 pathway.
| S-EPMC6038446 | biostudies-literature