SLC7A11 regulated by NRF2 modulates esophageal squamous cell carcinoma radiosensitivity by inhibiting ferroptosis

Abstract

Background Solute carrier family 7 member 11(SLC7A11) is a component of cysteine/glutamate transporter, which plays a key role in tumor growth; however, its underlying effect on radiosensitivity in esophageal squamous cell carcinoma (ESCC) remains unclear. This study aimed to clarify SLC7A11’s expression and correlation with nuclear expression of nuclear factor erythroid-2 (NRF2)-associated radioresistance in ESCC. Methods We included 127 ESCC patients who received radical chemoradiotherapy. Immunohistochemical staining was used to detect SLC7A11 and NRF2 nuclear expression, and the relationship between clinicopathological characteristics and survival rates or therapy response were evaluated. Western blot, dual-reporter assays and Chromatin immunoprecipitation (ChIP)-sequencing were used to analyze their relationship in vitro. Their roles in radioresistance were then investigated through multiple validation steps. Results NRF2 nuclear expression and SLC7A11 expression were overexpressed in ESCC tissues and were positively correlated with one another. NRF2 nuclear expression was significantly associated with tumor length, lymph node metastasis, and TNM stage, while SLC7A11 expression was associated with lymph node metastasis. Patients with high NRF2 nuclear expression and SLC7A11 expression had significantly shorter overall and progression-free survival, and poor treatment response. The multivariate model showed that NRF2 nuclear expression and SLC7A11 expression, sex and tumor location are independent prognostic factors. In vitro analysis confirmed that hyperactivation of NRF2 induced SLC7A11 expression by directly binding to its promoter region, promoting radioresistance, reducing radiotherapy-induced lipid peroxidation levels, PTGS2 expression, and radiotherapy-related ferroptosis morphologic features. Conclusion Our study reveals a connection between high SLC7A11 expression and NRF2 nuclear expression in patients with ESCC that was related to worse survival and poorer therapy outcomes. SLC7A11-mediated ferroptosis inhibition induced NRF2-associated radioresistance, highlighting potential of NRF2/SLC7A11/ferroptosis axis as future therapeutic targets against therapy resistance biomarker.

Contribution of Lipid Oxidation and Ferroptosis to Radiotherapy Efficacy

“…Corroborating this preclinical data, high NRF2 and SLC7A11 expression has been associated with diminished radiotherapy induced ferroptosis and decreased lipid oxidation, as well as radiotherapy resistance in patients with esophageal cancer [48]. In head and neck cancer, treatment with artesunate to inhibit NRF2 increased ferroptosis in cancer cells [49].…”

Plasmodium berghei-Mediated NRF2 Activation in Infected Hepatocytes Enhances Parasite Survival

“…Furthermore, the negative regulator of ferroptosis, SLC7a11 was shown to be important for liver stage development [44]. Interestingly, expression of SLC7a11 is regulated by NRF2 [48] confirming that the presence of the parasite regulates the oxidative state of its host cell. Since NRF2 functions in inhibiting ferroptosis mainly by controlling intracellular oxidation homeostasis [49][50][51], it will be interesting to investigate whether there is a…”

Molecular pathways associated with oxidative stress and their potential applications in radiotherapy (Review)

“…cells via activation of specific downstream regulator target genes, including SLc7A11. These genes aim to prevent oxidative damage (68)(69)(70)(71). In addition, the Trx system may also protect cells from lipid peroxidation (72).…”