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

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 (ERO1 alpha) 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 ERO1 alpha 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 ERO1 alpha 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 ERO1 alpha 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 ERO1 alpha is a functional downstream target of mTORC1. Elevated ERO1 alpha induced ferroptosis resistance and exerted pro-oncogenic roles in mTORC1-activated cells via upregulation of SLC7A11. Mechanically, ERO1 alpha stimulated the transcription of SLC7A11 by activating the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway. Moreover, ERO1 alpha inhibition combined with treatment using the ferroptosis inducer IKE exhibited synergistic antitumor effects on mTORC1-activated tumors. Conclusions The ERO1 alpha/IL-6/STAT3/SLC7A11 pathway is crucial for mTORC1-mediated ferroptosis resistance and tumor growth, and combining ERO1 alpha inhibition with ferroptosis inducers is a novel and effective treatment for mTORC1-related tumors.