2. Academic Validation
  3. Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11

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

  • J Exp Clin Cancer Res. 2024 Apr 13;43(1):112. doi: 10.1186/s13046-024-03039-2.
Zixi Wang # 1 2,  Huaiyuan Zong # 1,  Weiwei Liu # 3,  Wei Lin # 4,  Anjiang Sun 1,  Zhao Ding 3,  Xu Chen 1,  Xiaofeng Wan 5,  Yanyan Liu 6,  Zhongdong Hu 7,  Hongbing Zhang 8,  Hongwu Li 3 9,  Yehai Liu 3,  Dapeng Li 10,  Sumei Zhang 11,  Xiaojun Zha 12 13
Affiliations

Affiliations

  • 1 Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, No. 81 Meishan Road, Hefei, 230032, Anhui Province, China.
  • 2 Children's Hospital of Fudan University, National Children's Medical Center, And Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
  • 3 Department of Otorhinolaryngology, Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
  • 4 Department of Stomatology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
  • 5 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China.
  • 6 Department of Thyroid and Breast Surgery, Hefei First People's Hospital, Hefei, 230061, China.
  • 7 Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
  • 8 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.
  • 9 Anhui Public Health Clinical Center, Hefei, 230011, China.
  • 10 Department of Otorhinolaryngology, Head & Neck Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, No. 616 Duzhong Road, Bozhou, 236800, Anhui Province, China. ldpeagle1@163.com.
  • 11 Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, No. 81 Meishan Road, Hefei, 230032, Anhui Province, China. zhangsumei@ahmu.edu.cn.
  • 12 Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, No. 81 Meishan Road, Hefei, 230032, Anhui Province, China. zhaxiaojunpumc@gmail.com.
  • 13 Department of Otorhinolaryngology, Head & Neck Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, No. 616 Duzhong Road, Bozhou, 236800, Anhui Province, China. zhaxiaojunpumc@gmail.com.
  • # Contributed equally.
PMID: 38610018 DOI: 10.1186/s13046-024-03039-2
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.

Keywords

ERO1α; Ferroptosis; SLC7A11; Tumor growth; mTOR.

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