Arsenic trioxide suppresses lung adenocarcinoma stem cell stemness by inhibiting m6A modification to promote ferroptosis
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ABSTRACT:
SUBMITTER: Jin W
PROVIDER: S-EPMC10915325 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:To understand if there exists a functional interaction between arsenic trioxide and paclitaxel in vitro.HeLa and HCT116 (rho53(+/+) and rho53(-/-)) cells were treated with As2O3 and/or paclitaxel for various times. Treated cells were collected for analyses using a combination of flow cytometry, fluorescence microscopy and Western blotting.Because As(2)O(3) is capable of inhibiting tubulin polymerization and inducing mitotic arrest, we examined whether there existed any functional interaction between As(2)O(3) and paclitaxel, a well-known microtubule poison. Flow cytometry and fluorescence microscopy revealed that although As(2)O(3) alone caused a moderate level of mitotic arrest, it greatly attenuated paclitaxel-induced mitotic arrest in cells with p53 deficiency. Western blot analysis showed that As(2)O(3) significantly blocked phosphorylation of BubR1, Cdc20, and Cdc27 in cells treated with paclitaxel, suggesting that arsenic compromised the activation of the spindle checkpoint. Our further studies revealed that the attenuation of paclitaxel-induced mitotic arrest by As(2)O(3) resulted primarily from sluggish cell cycle progression at S phase but not enhanced mitotic exit.The observations that As(2)O(3) has a negative impact on the cell cycle checkpoint activation by taxol should have significant clinical implications because the efficacy of taxol in the clinics is associated with its ability to induce mitotic arrest and subsequent mitotic catastrophe.
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Project description:Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC); nonetheless, radioresistance remains the leading cause of localized recurrence. Our study demonstrates a significant increase in the N6-methyladenosine (m6A) methylase METTL3 in NPC and other tumors. Mechanistically, METTL3 acts as an m6A methylase, enhancing the m6A modification of the solute carrier family 7 member 11 (SLC7A11) transcript, which increases its stability and expression, thereby inhibiting radiation-induced ferroptosis and ultimately inducing radioresistance in NPC. Furthermore, silencing SLC7A11 or employing the ferroptosis inducer Erastin negated the promoting effect of METTL3 on NPC cell radioresistance. These findings suggest that METTL3 could be a novel therapeutic target for overcoming radiotherapy resistance in NPC.
| S-EPMC11844296 | biostudies-literature
Project description:Arsenic trioxide (ATO) is a well-accepted chemotherapy agent in managing promyelocytic leukemia. ATO often causes severe health hazards such as hepatotoxicity, dermatosis, neurotoxicity, nephrotoxicity and cardiotoxicity. The production of reactive oxygen species, (ROS) play a significant role in ATO-induced hepatotoxicity. The oral hypoglycemic drug, metformin, is considered to be a potential novel agent for chemoprevention in the treatment of cancer. Moreover, metformin has also been shown to have hepatoprotective effects. In the present study, we demonstrated that metformin protected normal hepatocytes from ATO-induced apoptotic cell death in vitro and in vivo. Gene expression screening revealed that glucose metabolism might be related to the metformin-induced protective effect on ATO-treated AML12 cells. The metformin-promoted or induced glycolysis was not responsible for the protection of AML12 cells from ATO-induced apoptotic cell death. Instead, metformin increased the intracellular NADH/NAD+ ratio by inhibiting mitochondrial respiratory chain complex I, further decreasing the intracellular ROS induced by ATO. Treatment with low glucose or rotenone, a mitochondrial respiratory chain complex I inhibitor, also protected AML12 cells from ATO-induced apoptotic cell death. We show for the first time that metformin protects the hepatocyte from ATO by regulating the mitochondrial function. With its properties of chemoprevention, chemosensitization and the amelioration of liver damage, metformin has great prospects for clinical application other than type 2 diabetes mellitus (T2DM).
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Project description:The aim is to explore the underlying mechanism of basic leucine zipper ATF-like transcription factor 2 (BATF2) in tongue squamous cell carcinoma (TSCC). The expression of BATF2 in TSCC tissues and corresponding adjacent normal TSCC tissues, human TSCC cell lines (SCC-15 and CAL-27) and human normal tongue epithelial cells NTEC was detected. Then, SCC-15 cells with stable BATF2 knockdown and CAL-27 cells with BATF2 overexpression were established to investigate the functional effect of BATF2 on TSCC. Thereafter, the effect of BATF2 on TSCC angiogenesis and BATF2 m6A methylation was also examined. BATF2 was significantly downregulated in TSCC tissues and cell lines, and BATF2 overexpression could suppress growth, metastasis and angiogenesis of TSCC. Mechanistically, vascular endothelial growth factor A (VEGFA) was identified as a downstream gene of BATF2, and it was confirmed that BATF2 suppressed growth, metastasis and angiogenesis of TSCC via inhibiting VEGFA. In addition, the N6-methyladenosine (m6A) modification of BATF2 mRNA mediated by METTL14 suppressed its expression in TSCC. METTL14/BATF2 axis could serve as a novel promising therapeutic candidate against angiogenesis for TSCC.
| S-EPMC9769451 | biostudies-literature
Project description:ATO is a therapeutic agents used to treat APL, a disease caused by a chromosomal translocation of the RARα gene that can occur reciprocally with the PML gene. The mechanisms through which ATO function and how increased levels of ATO adversely affect the cell are not fully characterized though they involve the SUMOylation, the ubiquitylation and the degradation of the PML/RARα oncoprotein through the PML moiety. Changes in protein SUMOylation, phosphorylation and ubiquitylation were profiled using large-scale proteomic workflows on HEK293 cells following exposure to typical (1 μM) or elevated (10 μM) ATO for 4h to understand the mechanism that underlies the cytotoxicity induced with important ATO levels. Our analyses revealed that 88 proteins displayed divergent SUMOylation with elevated ATO compared to the lower dose, where the latter caused changes in SUMOylation of 4 proteins, including PML. Some of these differing SUMOylation events occurred on known substrates of caspase-3. A similar phenomenon was observed in the phosphoproteomic studies, where 48 proteins were specifically regulated with elevated ATO levels, while low ATO doses barely altered the phosphoproteome. Elevated levels of ATO cause the erroneous SUMOylation and phosphorylation of a vast amount of substrates, which may be responsible for its cytotoxic effects.
2020-04-06 | PXD016166 | Pride
Project description:Poly (ADP-ribose) polymerase (PARP) inhibitors are efficacious in treating platinum-sensitive ovarian cancer (OC), but demonstrate limited efficiency in patients with platinum-resistant OC. Thus, further investigations into combined strategies that enhance the response to PARP inhibitors (PARPi) in platinum-resistant OC are required. The present study aimed to investigate the combined therapy of arsenic trioxide (ATO) with olaparib, a common PARPi, and determine how this synergistic cytotoxicity works in platinum-resistant OC cells. Functional assays demonstrated that the combined treatment of olaparib with ATO significantly suppressed cell proliferation and colony formation, and enhanced DNA damage as well as cell apoptosis in A2780-CIS and SKOV3-CIS cell lines. Results of the present study also demonstrated that a combination of olaparib with ATO increased lipid peroxidation and eventually triggered ferroptosis. Consistently, the combined treatment synergistically suppressed tumor growth in mice xenograft models. Mechanistically, ATO in combination with olaparib activated the AMPK α pathway and suppressed the expression levels of stearoyl-CoA desaturase 1 (SCD1). Collectively, results of the present study demonstrated that treatment with ATO enhanced the effects of olaparib in platinum-resistant OC.
| S-EPMC9513087 | biostudies-literature
Project description:Boosting tumor immunosurveillance with vaccines has been proven to be a feasible and cost-effective strategy to fight cancer. Although major breakthroughs have been achieved in preventative tumor vaccines targeting oncogenic viruses, limited advances have been made in curative vaccines for virus-irrelevant malignancies. Accumulating evidence suggests that preconditioning tumor cells with certain cytotoxic drugs can generate whole-cell tumor vaccines with strong prophylactic activities. However, the immunogenicity of these vaccines is not sufficient to restrain the outgrowth of existing tumors. In this study, we identified arsenic trioxide (ATO) as a wide-spectrum cytotoxic and highly immunogenic drug through multiparameter screening. ATO preconditioning could generate whole-cell tumor vaccines with potent antineoplastic effects in both prophylactic and therapeutic settings. The tumor-preventive or tumor-suppressive benefits of these vaccines relied on CD8+ T cells and type I and II interferon signaling and could be linked to the release of immunostimulatory danger molecules. Unexpectedly, following ATO-induced oxidative stress, multiple cell death pathways were activated, including autophagy, apoptosis, necroptosis, and ferroptosis. CRISPR‒Cas9-mediated knockout of cell death executors revealed that the absence of Rip3, Mlkl, or Acsl4 largely abolished the efficacy of ATO-based prophylactic and therapeutic cancer vaccines. This therapeutic failure could be rescued by coadministration of danger molecule analogs. In addition, PD-1 blockade synergistically improved the therapeutic efficacy of ATO-based cancer vaccines by augmenting local IFN-γ production.
| S-EPMC9794749 | biostudies-literature
Project description:METTL14 functions as an RNA methyltransferase involved in m6A modification, influencing mRNA biogenesis, decay, and translation processes. However, the specific mechanism by which METTL14 regulates glucose-6-phosphate dehydrogenase (G6PD) to promote the progression of lung adenocarcinoma (LUAD) is not well understood. Quantitative measurement and immunohistochemistry (IHC) analysis have demonstrated higher levels of m6A in LUAD tissues compared to adjacent normal tissues. Additionally, the expression of METTL14 was significantly increased in LUAD tissues. In LUAD cell lines, both METTL14 and m6A levels were elevated compared to normal human lung epithelial cells. Knockdown of METTL14 markedly reduced LUAD cell proliferation, migration, and invasion. Conversely, overexpression of METTL14, but not the mutant form, significantly enhanced these cellular processes in LUAD. In vivo studies using nude mice with subcutaneously transplanted LUAD cells demonstrated that stable METTL14 knockdown led to notably reduced tumor volume and weight, along with fewer Ki67-positive cells and lung metastatic sites. Importantly, METTL14 knockdown reduced glycolytic activity in LUAD cells. Through a combination of RNA sequencing and MeRIP-sequencing, we identified numerous altered genes and confirmed that IGF2BP2 enhances G6PD mRNA stability after METTL14-mediated m6A modification, thereby promoting tumor growth and metastasis. Moreover, LUAD patients with higher levels of G6PD had poorer overall survival (OS). In conclusion, our study indicates that METTL14 upregulates G6PD expression post-transcriptionally through an m6A-IGF2BP2-dependent mechanism, thereby stabilizing G6PD mRNA. These findings propose potential diagnostic biomarkers and effective targets for anti-metabolism therapy in LUAD.
| S-EPMC11322390 | biostudies-literature
Project description:BackgroundGastric cancer (GC) is one of the most pernicious tumors that seriously harm human healthcare. GC metastasis is one of the prime cause of failed cancer treatment, but correlation between N6-methyladenosine (m6A) and GC metastasis was less reported.MethodsMethylated RNA immunoprecipitation sequencing (MeRIP-seq) of GC tissues was conducted. Quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry (IHC) were taken to determine the expression of ALKBH5 in GC tissues and cell lines. RNA-seq together with MeRIP-qRT-PCR was used to screen the target gene of ALKBH5. RNA pulldown, mass spectrometry and RNA immunoprecipitation (RIP) were used to search the "reader" protein of target gene. The mechanism was also validated via a tail vein injection method for lung metastasis model.ResultsDecreased expression of ALKBH5 was detected in GC samples, and it was correlated with clinical tumor distal metastasis and lymph node metastasis. ALKBH5 interference promoted metastasis of GC cells and this effect was closely related to the demethylase activity of ALKBH5. PKMYT1, as a downstream target of ALKBH5, promoted invasion and migration in GC. Caused by ALKBH5 knockdown or its demethylase activity mutation, upregulated expression of PKMYT1 indicated that ALKBH5 modulates expression of PKMYT1 in an m6A-dependent manner. IGF2BP3 helped stabilize the mRNA stability of PKMYT1 via its m6A modification site.ConclusionsThis study established an ALKBH5-PKMYT1-IGF2BP3 regulation system in metastasis, representing a new therapeutic target for GC metastasis.
| S-EPMC8812266 | biostudies-literature
Project description:BackgroundCancer-associated fibroblasts (CAFs) have been reported that can affect cancer cell proliferation, metastasis, ferroptosis, and immune escape. METTL3-mediated N6-methyladenine (m6A) modification is involved in the tumorigenesis of colorectal cancer (CRC). Herein, we investigated whether METTL3-dependent m6A in CAFs-derived exosomes (exo) affected CRC progression.MethodsqRT-PCR and western blotting analyses detected levels of mRNAs and proteins. Cell proliferation and metastasis were evaluated using MTT, colony formation, transwell, and wound healing assays, respectively. Cell ferroptosis was assessed by detecting cell viability and the levels of Fe+, reactive oxygen species, and glutathione after erastin treatment. Exosomes were isolated from CAFs by ultracentrifugation. The m6A modification profile was determined by methylated RNA immunoprecipitation assay and the interaction between METTL3 and ACSL3 (acyl-CoA synthetase 3) was verified using dual-luciferase reporter assay. Animal models were established for in vivo analysis.ResultsCAFs promoted CRC cell proliferation and metastasis, and suppressed cell ferroptosis. METTL3 was enriched in CAFs and was packaged into exosomes. The m6A modification and METTL3 expression were increased in CRC samples. Knockdown of METTL3 in CAFs-exo suppressed CRC cell proliferation and metastasis, and induced cell ferroptosis. Mechanistically, METTL3 induced ACSL3 m6A modification and stabilized its expression. The anticancer effects mediated by METTL3-silenced CAFs-exo could be rescued by ACSL3 overexpression. Moreover, in vivo assay also showed that CAFs-exo with decreased METTL3 could hinder CRC growth and metastasis in mice models.ConclusionCAFs promoted the proliferation and metastasis, and restrained the ferroptosis in CRC by exosomal METTL3-elicited ACSL3 m6A modification.
| S-EPMC11331890 | biostudies-literature