Dichloroacetate attenuates the stemness of colorectal cancer cells via trigerring ferroptosis through sequestering iron in lysosomes

Sun, Jie; Cheng, Xianzhong; Pan, Shubo; Wang, Liangjing; Dou, Wenhuan; Liu, Jie; Shi, Xiaohua

doi:10.1002/tox.23057

Cited by 45 publications

(30 citation statements)

References 39 publications

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“…Subsequently, targeting iron in lysosomes was confirmed to CSC by different studies, 29‐32 and combined use of chemotherapy and salinomycin can boost the capacity of salinomycin to kill CSC and both CSCs and tumor cells are killed 33,34 . Thus, we wonder whether DCA could target iron homeostasis to kill HCC stem cells, this mechanism has been shown in colorectal cancer cells 24 . What's more, based on the KEGG enrichment analysis, some other cancer‐related pathways are also enriched in HCC cells with DCA treatment, such as PI3K‐Akt signaling pathway, which had been shown to be involved in limonin‐mediated inhibition on 35 ; and FOXO signaling pathway, p53 signaling pathway, TNF signaling pathway PPAR signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

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Dichloroacetate attenuates the stemness of hepatocellular carcinoma cells via promoting nucleus‐cytoplasm translocation of YAP

Zhifang

2021

Environmental Toxicology

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The antitumor effects of dichloroacetate (DCA) have been widely explored, however, its roles in hepatocellular carcinoma (HCC) progression are still unclear. In the current work, we found that DCA had little effects on HCC cell viability, but could attenuate the stemness of HCC cells, which is evident by decreasing the tumor sphere‐formation ability, ALDH activity and the expression of stemness critical regulators. Mechanistic studies based on RNA‐sequencing data showed that DCA activated the Hippo pathway. Furthermore, we indicated that DCA promoted the nucleus‐cytoplasm translocation of YAP, but not TAZ, another critical executor of Hippo pathway. Moreover, suppressing of Hippo pathway using XMU‐MP‐1, an inhibitor of Hippo pathway, partially abrogated DCA‐induced inhibitory effects on HCC cell stemness. This work suggests that DCA might be a potential inhibitor for HCC progression.

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Section: Discussionmentioning

confidence: 99%

“…In consistent, DCA‐mediated effects on the stemness of cancer cells were first revealed in pancreatic cancer cells 16 . Notably, a recent study indicates that DCA can also attenuate the stemness of colorectal cancer cells 24 . However, its roles in HCC progression are never been demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Dichloroacetate attenuates the stemness of hepatocellular carcinoma cells via promoting nucleus‐cytoplasm translocation of YAP

Zhifang

2021

Environmental Toxicology

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“…Targeting iron metabolism using the iron nanoparticles can be used to treat cancer through ferroptosis, which has been approved by FDA [32] . Besides, inducing ferroptosis through sequenstering iron in lysosome has been con rmed to speci cally killing CSCs including BCSCs [10,20,22,23] . In this work, we found CPUL119, CPUL129 and CPUL149 could increase the content of iron in breast cancer cells accompanying with the change of iron-regulatory protein such as IRP2, TfR1 and ferritin.…”

Section: Discussionmentioning

confidence: 99%

“…Consistently, it has been shown that salinomycin and its drivatives could target BCSCs through sequestering iron in lysosomes [19][20][21] . Notably, targeting iron in lysosomes has been con rmed to killing CSCs in other tumors, such as nasopharyngeal carcinoma [22] and colorectal cancer [23] . These results amplify that sequestering iron in lysosomes is a promosing method in targeting BCSCs.…”

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confidence: 99%

Identification of A New Kind of Phenazine Compounds Attenuating The Stemness of Breast Cancer Cells Through Triggering Ferroptosis

Yang¹,

Lu²,

Zhang³

et al. 2021

Preprint

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Background: Breast cancer stem cells (BCSCs) are positively correlated with metastasis, chemoresistance and recurrence of breast cancer.Methods: The stemness were analyzed by qPCR and western blot, flow cytometry, cell spheroid formation assay, and tumor xenograft model. The cell viability was performed by MTT. The transcriptome analysis was used to evaluate the influence of these three compounds. The migration was analyzed by wound-healing assay, transwell invasion analysis, and metastasis model. The iron concentration was analyzed by fluorescence microscopy analysis. The lipid peroxidation and ROS level were analyzed by flow cytometry. The results were presented as mean ± SD, the analysis was Student’s t-test by using GraphPad Prism 5 software. P-values less than 0.05 were considered to be statistically significant. (*p < 0.05, **p < 0.01, ***p < 0.001).Results: Here, we tried to screen out small-molecule compounds targeting BCSCs from the phenazine library established by us before. We focused on the compounds without affecting cell viability and screened out three potential compounds (CPUL119, CPUL129, CPUL149) that can significantly attenuate the stemness of breast cancer cells, as evident by the decrease of stemness marker expression, CD44+/CD24- subpopulation, mammary spheroid-formation ability and tumor-initiating capacity. Additionally, these compounds suppressed the metastatic ability of breast cancer cells in vitro and in vivo. Combined with the transcriptome-sequencing analysis in breast cancer cells with or without the treatment of these three compounds, respectively, it was found that ferroptosis was shown on the top of the most upregulated pathways by CPUL119, CPUL129 and CPUL149. Mechanistically, we found that CPUL119, CPUL129 and CPUL149 could trigger ferroptosis by accumulating and sequestering iron in lysosomes through interacting with iron, and by regulating the expression of proteins (IRP2, TfR1, ferritin) engaged in modulating iron transport and storage. Furthermore, inhibition of ferroptosis rescued the suppression of these three compounds on the stemness of breast cancer cells. Conclusions: This study suggests that CPUL119, CPUL129 and CPUL149 can specifically inhibit the stemness of breast cancer cells through ferroptosis and may be the potential compounds for breast cancer treatment.

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“…Scholars have suggested that ferroptosis may be adaptive strategy used for eliminating cancerous cells and hence prevent cancer development in situations of infections, cellular stress, and nutrient de ciency [6]. Previous research has reported that some inducers, such as RSL3 [7], β-elemene [8], Resibufogenin [9], andrographis [10], bromelain [11], IMCA [12], talaroconvolutin A (TalaA) [13], ACADSB [14], erastin [15], dichloroacetate [16], and B. etnensis Raf. extract [17] suppressed the progression of CRC via inducing ferroptosis.…”

Section: Introductionmentioning

confidence: 99%

A Novel Ferroptosis-related Lncrna Prognostic Signature for Colorectal Cancer by Bioinformatics Analysis

Yang

Zhang

Wang

et al. 2021

Preprint

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Background: Recently, extensive studies have shown that ferroptosis in cancer treatment has been increasingly confirmed. The current study aims to construct a robust ferroptosis-related lncRNAs signature prediction model of colorectal cancer (CRC) patients by bioinformatics analysisMethods: The transcriptome data were abstracted from The Cancer Genome Atlas (TCGA). Differentially expressed lncRNAs were screened by comparing 568 CRC tissues with 44 adjacent non-CRC tissues. Univariate Cox regression, lasso regression, multivariate Cox regression were conducted to design a ferroptosis-related lncRNA signature. This signature’s prognosis was verified by the log-rank test of Kaplan-Meier curve and the area under curve (AUC) of receiver operating characteristic (ROC) in train set, test set, and entire set. Furthermore, univariate and multivariate Cox regression were used to analyze its independent prognostic ability. The relationship of the ferroptosis-linked lncRNAs' expression and clinical variables was demonstrated by Wilcoxon rank-sum test and Kruskal-Wallis test. Gene set enrichment analysis (GSEA) was performed to signaling pathways it may involve.Results: 2541 differentially expressed lncRNAs were screened, of which 439 are ferroptosis-related lncRNAs. A seven ferroptosis-related lncRNAs (AC005550.2, LINC02381, AL137782.1, C2orf27A, AC156455.1, AL354993.2, AC008760.1) prognostic signature was constructed, validated and evaluated. This model's prognosis in the high-risk group is obviously worse than that of the low-risk group in train set, test set, and entire set. The AUC of ROC predicting the three years survival in the train set, test set, and entire set was 0.796, 0.715, and 0.758, respectively. Moreover, the designed molecular signature was found to be an independent prognostic variable. Compared to clinical variables, this signature's ROC curves demonstrated the second largest AUC value (0.737). The expression of these lncRNAs and the lncRNA signature are related to distant metastasis, Lymph-node status, clinical stage, T stage, KRAS mutation, BRAF mutation, MMR status, and perineural invasion. Finally, GSEA analysis results show that the signature is involved in six metabolism-related pathways.Conclusion: The current study constructed, validated, and evaluated a seven ferroptosis-related lncRNA signature which can independently be used to predict the prognosis of CRC patients, and it may become a new therapeutic target.

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Dichloroacetate attenuates the stemness of colorectal cancer cells via trigerring ferroptosis through sequestering iron in lysosomes

Cited by 45 publications

References 39 publications

Dichloroacetate attenuates the stemness of hepatocellular carcinoma cells via promoting nucleus‐cytoplasm translocation of YAP

Dichloroacetate attenuates the stemness of hepatocellular carcinoma cells via promoting nucleus‐cytoplasm translocation of YAP

Identification of A New Kind of Phenazine Compounds Attenuating The Stemness of Breast Cancer Cells Through Triggering Ferroptosis

A Novel Ferroptosis-related Lncrna Prognostic Signature for Colorectal Cancer by Bioinformatics Analysis

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