Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11

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Abstract

Background

The dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling plays a critical role in ferroptosis resistance and tumorigenesis. However, the precise underlying mechanisms still need to be fully understood.

Methods

Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) expression in mTORC1-activated mouse embryonic fibroblasts, cancer cells, and laryngeal squamous cell carcinoma (LSCC) clinical samples was examined by quantitative real-time PCR (qRT–PCR), western blotting, immunofluorescence (IF), and immunohistochemistry. Extensive in vitro and in vivo experiments were carried out to determine the role of ERO1α and its downstream target, member 11 of the solute carrier family 7 (SLC7A11), in mTORC1-mediated cell proliferation, angiogenesis, ferroptosis resistance, and tumor growth. The regulatory mechanism of ERO1α on SLC7A11 was investigated via RNA-sequencing, a cytokine array, an enzyme-linked immunosorbent assay, qRT–PCR, western blotting, IF, a luciferase reporter assay, and a chromatin immunoprecipitation assay. The combined therapeutic effect of ERO1α inhibition and the ferroptosis inducer imidazole ketone erastin (IKE) on mTORC1-activated cells was evaluated using cell line-derived xenografts, LSCC organoids, and LSCC patient-derived xenograft models.

Results

ERO1α is a functional downstream target of mTORC1. Elevated ERO1α induced ferroptosis resistance and exerted pro-oncogenic roles in mTORC1-activated cells via upregulation of SLC7A11. Mechanically, ERO1α stimulated the transcription of SLC7A11 by activating the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway. Moreover, ERO1α inhibition combined with treatment using the ferroptosis inducer IKE exhibited synergistic antitumor effects on mTORC1-activated tumors.

Conclusions

The ERO1α/IL-6/STAT3/SLC7A11 pathway is crucial for mTORC1-mediated ferroptosis resistance and tumor growth, and combining ERO1α inhibition with ferroptosis inducers is a novel and effective treatment for mTORC1-related tumors.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13046-024-03039-2.

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Most cited references 76

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Ferroptosis: mechanisms, biology and role in disease

Xuejun Jiang, Brent Stockwell, Marcus Conrad (2021)

The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.

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Ferroptosis as a p53-mediated activity during tumour suppression.

Richard Baer, Tongyuan Li, Ning Kon … (2015)

Although p53-mediated cell-cycle arrest, senescence and apoptosis serve as critical barriers to cancer development, emerging evidence suggests that the metabolic activities of p53 are also important. Here we show that p53 inhibits cystine uptake and sensitizes cells to ferroptosis, a non-apoptotic form of cell death, by repressing expression of SLC7A11, a key component of the cystine/glutamate antiporter. Notably, p53(3KR), an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence and apoptosis, fully retains the ability to regulate SLC7A11 expression and induce ferroptosis upon reactive oxygen species (ROS)-induced stress. Analysis of mutant mice shows that these non-canonical p53 activities contribute to embryonic development and the lethality associated with loss of Mdm2. Moreover, SLC7A11 is highly expressed in human tumours, and its overexpression inhibits ROS-induced ferroptosis and abrogates p53(3KR)-mediated tumour growth suppression in xenograft models. Our findings uncover a new mode of tumour suppression based on p53 regulation of cystine metabolism, ROS responses and ferroptosis.

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Is Open Access

Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal

Antonio Ayala, Mario F Muñoz, Sandro Argüelles (2014)

Lipid peroxidation can be described generally as a process under which oxidants such as free radicals attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs). Over the last four decades, an extensive body of literature regarding lipid peroxidation has shown its important role in cell biology and human health. Since the early 1970s, the total published research articles on the topic of lipid peroxidation was 98 (1970–1974) and has been increasing at almost 135-fold, by up to 13165 in last 4 years (2010–2013). New discoveries about the involvement in cellular physiology and pathology, as well as the control of lipid peroxidation, continue to emerge every day. Given the enormity of this field, this review focuses on biochemical concepts of lipid peroxidation, production, metabolism, and signaling mechanisms of two main omega-6 fatty acids lipid peroxidation products: malondialdehyde (MDA) and, in particular, 4-hydroxy-2-nonenal (4-HNE), summarizing not only its physiological and protective function as signaling molecule stimulating gene expression and cell survival, but also its cytotoxic role inhibiting gene expression and promoting cell death. Finally, overviews of in vivo mammalian model systems used to study the lipid peroxidation process, and common pathological processes linked to MDA and 4-HNE are shown.

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Author and article information

Contributors

Dapeng Li: ldpeagle1@163.com

Sumei Zhang: zhangsumei@ahmu.edu.cn

Xiaojun Zha:

ORCID: http://orcid.org/0000-0003-4006-0748

zhaxiaojunpumc@gmail.com

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J Exp Clin Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 13 April 2024

Publication date PMC-release: 13 April 2024

Publication date Collection: 2024

Volume: 43

Electronic Location Identifier: 112

Affiliations

[1 ]Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, ( https://ror.org/03xb04968) No. 81 Meishan Road, Hefei, 230032 Anhui Province China

[2 ]Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, ( https://ror.org/03t1yn780) Hefei, 230022 China

[3 ]Department of Stomatology, The First Affiliated Hospital of Anhui Medical University, ( https://ror.org/03t1yn780) Hefei, 230022 China

[4 ]Hefei Cancer Hospital, Chinese Academy of Sciences, ( https://ror.org/034t30j35) Hefei, 230031 China

[5 ]Department of Thyroid and Breast Surgery, Hefei First People’s Hospital, ( https://ror.org/05qwgjd68) Hefei, 230061 China

[6 ]Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, ( https://ror.org/05damtm70) Beijing, 100029 China

[7 ]GRID grid.506261.6, ISNI 0000 0001 0706 7839, State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, , Peking Union Medical College and Chinese Academy of Medical Sciences, ; Beijing, 100730 China

[8 ]Anhui Public Health Clinical Center, Hefei, 230011 China

[9 ]GRID grid.186775.a, ISNI 0000 0000 9490 772X, Department of Otorhinolaryngology, Head & Neck Surgery, , The Affiliated Bozhou Hospital of Anhui Medical University, ; No. 616 Duzhong Road, Bozhou, 236800 Anhui Province China

[10 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Children’s Hospital of Fudan University, National Children’s Medical Center, And Institutes of Biomedical Sciences, , Fudan University, ; Shanghai, 200032 China

Author information

Xiaojun Zha http://orcid.org/0000-0003-4006-0748

Article

Publisher ID: 3039

DOI: 10.1186/s13046-024-03039-2

PMC ID: 11015652

PubMed ID: 38610018

SO-VID: b9cacc57-9b66-4810-9113-6f92054de7d6

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 1 January 2024

Date accepted : 8 April 2024

Funding

Funded by: The Natural Science Foundation of China

Award ID: 81372475

Award ID: 82171127

Award ID: 82303021

Award Recipient : Yehai Liu Dapeng Li Xiaojun Zha

Funded by: Anhui Provincial Natural Science Foundation

Award ID: 2208085MH239

Award Recipient : Xiaojun Zha

Funded by: Natural Science Foundation of Universities of Anhui Province

Award ID: KJ2019A0219

Award Recipient : Xiaojun Zha

Funded by: Discipline Construction Project of the First Affiliated Hospital of Anhui Medical University

Award ID: No. 4245

Award Recipient : Yehai Liu

Funded by: 2020 Basic and Clinical Cooperative Research Promotion Program of Anhui Medical University

Award ID: 2020xkjT027

Award Recipient : Xiaojun Zha

Funded by: Anhui Medical University Affiliated Bozhou Hospital Talent Introduction Research Initiation Fund

Award ID: by2023058

Award Recipient : Dapeng Li

Funded by: ASHIPS Director's Fund

Award ID: YZJJ2022QN48

Award Recipient : Xiaofeng Wan

Funded by: Postgraduate Innovation Research and Practice Program of Anhui Medical University

Award ID: YJS20230027

Award Recipient : Zhao Ding

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: mtor,ferroptosis,ero1α,slc7a11,tumor growth

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: mtor, ferroptosis, ero1α, slc7a11, tumor growth

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Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11

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Abstract

Background

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Supplementary Information

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Karger: Oncology

Most cited references 76

Ferroptosis: mechanisms, biology and role in disease

Ferroptosis as a p53-mediated activity during tumour suppression.

Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal

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