Dataset Information

FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer.

ABSTRACT: Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse- and human-derived clinically relevant models and in a retrospective cohort of TNBC patients.

SUBMITTER: Lorito N

PROVIDER: S-EPMC11251055 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer.

Lorito Nicla N Subbiani Angela A Smiriglia Alfredo A Bacci Marina M Bonechi Francesca F Tronci Laura L Romano Elisabetta E Corrado Alessia A Longo Dario Livio DL Iozzo Marta M Ippolito Luigi L Comito Giuseppina G Giannoni Elisa E Meattini Icro I Avgustinova Alexandra A Chiarugi Paola P Bachi Angela A Morandi Andrea A

EMBO molecular medicine 20240626 7

Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are resp ...[more]

PMID: 38926633

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Project description:Triple-negative breast cancer (TNBC) presents limited therapeutic options and is characterized by a poor prognosis. Although Kinsenoside (KIN) possesses a wide range of pharmacological activities, its effect and mechanism in TNBC remain unclear. The objective of this research was to explore the therapeutic effectiveness and the molecular mechanisms of KIN on TNBC. Xenograft experiment was carried out to assess the impact of KIN on TNBC in vivo. The effect of KIN on TNBC in vitro was evaluated through the analysis of cell cytotoxicity and colony formation assays. Oil Red O staining and BODIPY 493/503 fluorescence staining were employed to detect the effect of KIN on lipid droplet (LD) formation. Transcriptomics and inhibitor-rescue experiments were conducted to investigate the role of KIN on TNBC. Mechanistic experiments, including quantitative real-time polymerase chain reaction (RT-qPCR), Western blotting, diacylglycerol acyltransferase 1 (DGAT1) overexpression assay, and flow cytometric assay, were employed to uncover the regulatory mechanisms of KIN on TNBC. KIN inhibited tumor growth without causing obvious toxicity to the liver and kidneys. In vitro experiments demonstrated that KIN significantly inhibited the viability and proliferation of TNBC cells, accompanied by decreased LD formation and lipid content. Polyunsaturated fatty acids (PUFAs) levels were significantly increased by KIN. Furthermore, transcriptomics and inhibitor-rescue experiments revealed that KIN induced ferroptosis in TNBC cells. KIN could significantly regulate ferroptosis-related proteins. Lipid peroxidation, iron accumulation, and GSH depletion also confirmed this. The LD inducer mitigated the KIN-induced ferroptosis in TNBC. The overexpression of DGAT1 attenuated the effects of KIN on cell viability and proliferation. Furthermore, the overexpression of DGAT1 inhibited the effect of KIN to trigger ferroptosis in TNBC cells. Our findings confirmed that KIN could trigger ferroptosis by suppressing DGAT1-mediated LD formation, thereby demonstrating a promising therapeutic effect of KIN in TNBC.

Project description:PurposeTriple-negative breast cancer (TNBC) is an aggressive tumor with poor prognosis, it has higher recurrence and metastatic rates than other breast cancer subtypes. This study aims to investigate biomarkers and potential targets for TNBC related to ferroptosis through data mining and bioinformatics analysis. The findings may provide new insights for treating TNBC.MethodsThe TNBC patients' data from the Cancer Genome Atlas (TCGA) database were extracted for differential expression and prognosis analysis. Consensus genes obtained by intersecting differential expressed and ferroptosis-related genes was used to establish the prognostic model by the univariate and multivariate Cox analyses. Besides, TNBC data from the Gene Expression Omnibus (GEO) database was used to confirm the reliability of the prognosis model. Moreover, clinical information was analyzed by multifactorial independent analysis to identify independent prognostic factors. The expression of genes constituting the prognostic model was further validated using the Human Protein Atlas (HPA) database. Finally, the Comparative Toxicogenomic Data (CTD) database was used to explore possible treatment drugs for TNBC.ResultsWe obtained 13,245 differential expressed genes, and 177 consensus genes. 98 genes with prognostic implication were obtained by univariable Cox. Then, a prognostic model including 12 ferroptosis-related genes was constructed by multivariable Cox. The area under curve (AUC) value of the prognostic model for TNBC was 0.82. The GEO database validated that the model (AUC = 0.77) could predict the patient outcomes. The staining results of 10 out of 12 prognostic model genes in HPA database showed that their expression was consistent with our predictions. Clinical risk analysis indicated that risk score of patients could act as an independent prognostic factor. Finally, six drugs that may have interaction with 12 ferroptosis-related genes were obtained using the CTD database.ConclusionThe prognostic model composed of 12 ferroptosis-related genes could predict the prognosis of TNBC patients, and seven genes (ASNS, LAMP2, CAV1, DPP4, HELLS, TF, ZFP69B) could be potential new therapeutic targets for TNBC, and two drugs (1-methyl-3-isobutylxanthine, rosiglitazone) could act as potential therapeutic drugs for the treatment of TNBC.

Dataset Information

FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer.

Publications

FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer.

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