GDF15 knockdown promotes erastin-induced ferroptosis by decreasing SLC7A11 expression

Chen, Liang; Qiao, Linlin; Bian, Yue; Sun, Xiuju

doi:10.1016/j.bbrc.2020.03.079

Cited by 56 publications

(40 citation statements)

References 31 publications

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“…Thus, the specific role of DPP4 in ferroptosis process in LUAD still need to be further studied. According to the study of GDF15 (growth differentiation factor 15) in gastric cancer cell line MGC803, GDF15 functions as a ferroptosis inhibitor in gastric cancer, for knockdown of GDF15 could promote erastin-induced ferroptosis by reducing the expression of SLC7A11 ( Chen L. et al, 2020 ). However, GDF15 was identified as a protective factor for LUAD patients according to the univariate Cox analysis, and how GDF15 functions by ferroptosis process in lung cancer has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of a Ferroptosis-Related Gene Signature for Overall Survival Prediction in Lung Adenocarcinoma

Tian

Zhou

Zhu

et al. 2021

Front. Cell Dev. Biol.

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Background: Ferroptosis is an iron-dependent programmed cell death process. Recent studies have found that ferroptosis inducers hold promising potential in the treatment of lung adenocarcinoma (LUAD). However, the comprehensive analysis about the prognostic value of ferroptosis-related genes in LUAD remains to be elucidated.Methods: The RNA sequencing data and corresponding clinical information were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A total of 259 ferroptosis-related genes were extracted from FerrDb website. The ferroptosis-related prognostic signature was developed by least absolute shrinkage and selection operator (LASSO) Cox regression analysis in TCGA LUAD cohort, and then validated by 5 independent GEO cohorts. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were performed to identify the difference in biological processes and functions between different risk groups. The expression levels of core prognostic genes were then verified in LUAD samples by immunohistochemistry (IHC) and erastin-treated LUAD cell lines by real-time polymerase chain reaction (PCR). The potential roles of GPX2 and DDIT4 as ferroptosis drivers in LUAD cell line were further confirmed by in vitro experiments.Results: A total of 20 intersecting genes between 70 ferroptosis-related DEGs and 45 potential prognostic genes were obtained for LASSO Cox regression analysis. The ferroptosis-related prognostic signature was developed by 7 core prognostic DEGs, and stratified LUAD patients into two risk groups. Kaplan-Meier analysis showed that the overall survival (OS) of LUAD patients in the high-risk group was significantly worse than that of the low-risk group. External validation of 5 independent GEO cohorts further confirmed that the ferroptosis-related prognostic signature was an ideal biomarker for predicting the survival of LUAD patients. Significant enrichment of fatty acid metabolism and cell cycle-related pathways were found in different risk groups. The expression patterns of 7 core prognostic genes in LUAD and adjacent normal lung tissues were validated by IHC, which was almost consistent with the results from public database. Furthermore, the changes related to cell cycle and ferroptosis after erastin treatment were also validated in LUAD cell lines. In addition, silencing GPX2 or DDIT4 could partially reverse the erastin-induced ferroptosis.Conclusion: In summary, the ferroptosis-related prognostic signature based on 7 core prognostic DEGs indicated superior predictive performance of LUAD patients. Targeting ferroptosis holds potential to be a therapeutic alternative for LUAD.

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Section: Discussionmentioning

confidence: 99%

Development and Validation of a Ferroptosis-Related Gene Signature for Overall Survival Prediction in Lung Adenocarcinoma

Tian

Zhou

Zhu

et al. 2021

Front. Cell Dev. Biol.

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“…Our discoveries evidenced that TalaA is a potent blocker of the SLC7A11-GSS-GSH axis, which is positively associated with ferroptosis. Other research has also been focused on the use of SLC7A11 as a target molecule for ferroptosis promotion 40 .…”

Section: Discussionmentioning

confidence: 99%

Discovery of a novel ferroptosis inducer-talaroconvolutin A—killing colorectal cancer cells in vitro and in vivo

Xia

Liu

et al. 2020

Cell Death Dis

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Ferropotsis is among the most important mechanisms of cancer suppression, which could be harnessed for cancer therapy. However, no natural small-molecule compounds with cancer inhibitory activity have been identified to date. In the present study, we reported the discovery of a novel ferroptosis inducer, talaroconvolutin A (TalaA), and the underlying molecular mechanism. We discovered that TalaA killed colorectal cancer cells in dose-dependent and time-dependent manners. Interestingly, TalaA did not induce apoptosis, but strongly triggered ferroptosis. Notably, TalaA was significantly more effective than erastin (a well-known ferroptosis inducer) in suppressing colorectal cancer cells via ferroptosis. We revealed a dual mechanism of TalaA’ action against cancer. On the one hand, TalaA considerably increased reactive oxygen species levels to a certain threshold, the exceeding of which induced ferroptosis. On the other hand, this compound downregulated the expression of the channel protein solute carrier family 7 member 11 (SLC7A11) but upregulated arachidonate lipoxygenase 3 (ALOXE3), promoting ferroptosis. Furthermore, in vivo experiments in mice evidenced that TalaA effectively suppressed the growth of xenografted colorectal cancer cells without obvious liver and kidney toxicities. The findings of this study indicated that TalaA could be a new potential powerful drug candidate for colorectal cancer therapy due to its outstanding ability to kill colorectal cancer cells via ferroptosis induction.

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“…Inhibition of glucose-regulated protein 78 (GRP78), one of the most active molecular chaperone components in the ER of cancer cells, could enhance the effect of artesunate-induced ferroptosis in KRAS mutant pancreatic cancer cells ( 174 ). Growth/differentiation factor 15 (GDF15) knockdown has been shown to promote erastin-induced ferroptosis in MGC803 cells by attenuating SLC7A11 expression and subsequently decreasing intracellular GSH levels ( 179 ).…”

Section: Ferroptosis and Cancermentioning

confidence: 99%

Ferroptosis: Biochemistry and Biology in Cancers

et al. 2021

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The challenge of eradicating cancer is that cancer cells possess diverse mechanisms to protect themselves from clinical strategies. Recently, ferroptosis has been shown to exhibit appreciable anti-tumor activity that could be harnessed for cancer therapy in the future. Ferroptosis is an iron-dependent form of regulated cell death that is characterized by the oxidization of polyunsaturated fatty acids (PUFAs) and accumulation of lipid peroxides. Ferroptosis has been closely correlated with numerous biological processes, such as amino acid metabolism, glutathione metabolism, iron metabolism, and lipid metabolism, as well as key regulators including GPX4, FSP1, NRF2, and p53. Although ferroptosis could be involved in killing various cancer cells, multiple aspects of this phenomenon remain unresolved. In this review, we summarize the biochemistry and biology of ferroptosis in diverse cancers and discuss the potential mechanisms of ferroptosis, which might pave the way for guiding cancer therapeutics.

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GDF15 knockdown promotes erastin-induced ferroptosis by decreasing SLC7A11 expression

Cited by 56 publications

References 31 publications

Development and Validation of a Ferroptosis-Related Gene Signature for Overall Survival Prediction in Lung Adenocarcinoma

Development and Validation of a Ferroptosis-Related Gene Signature for Overall Survival Prediction in Lung Adenocarcinoma

Discovery of a novel ferroptosis inducer-talaroconvolutin A—killing colorectal cancer cells in vitro and in vivo

Ferroptosis: Biochemistry and Biology in Cancers

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