Although we previously reported that Nrf2-mediated-antioxidant pathways play an important role in radiosensitivity in OSCC 10, the detailed mechanisms have not been fully elucidated. Moreover, the Nrf2-mediated-antioxidant pathway is implicated in the chemoresistance and radioresistance of several malignancies, including OSCC 1, 9. Recent studies revealed that activated Nrf2 is a key transcription factor associated with tumor development and progression in various cancers, including head and neck cancer 5, 6, 7, 8. Following cellular exposure to oxidative stress, Nrf2 escapes Keap1-mediated repression and translocates to the nucleus, in which it induces the transcription of numerous cytoprotective genes 4. Under basal conditions, Nrf2 is sequestered in the cytoplasm by its repressor Keap1 and constitutively degraded through the ubiquitin–proteasome pathway 4. The nuclear factor erythroid 2-related factor 2 (Nrf2)–Kelch-like ECH-associated protein 1 (Keap1) signaling pathway is one of the main cellular defense mechanisms against oxidative stress 4. Moreover, the development of new treatment strategies is crucial. Additionally, to improve patient outcomes, it is extremely important to explore novel biomarkers for guiding therapeutic management and predicting prognosis of OSCC. Therefore, to improve the efficacy of radiotherapy, clarification of the characteristics of radioresistant OSCC cells is an important goal in radiation biology. Generally, cancer cells with antioxidant activity can escape the damaging effects of radiation by scavenging ROS, thereby leading to radioresistance 3. However, treatment is often confounded by tumor resistance to radiotherapy, similarly as observed for surgical resection and chemotherapy 2. Radiotherapy is an important treatment modality for head and neck cancers, including oral squamous cell carcinoma (OSCC), which effectively ablates cancer cells by causing DNA damage through the generation of reactive oxygen species (ROS) 1. Targeting Nrf2 antioxidant pathway may represent a promising treatment strategy for highly malignant OSCC. Our results suggest that Nrf2 plays an important role in the radioresistance of OSCC accompanied by metabolic reprogramming. Additionally, p-Nrf2 expression was closely related to the pathological response to chemoradiotherapy, and its expression was predictive of prognosis in patients with advanced OSCC. The enhancement of Nrf2-dependent glycolysis and glutathione synthesis was involved in the development of radioresistance. Moreover, elevated Nrf2 expression was associated with radioresistance. Nrf2 was stably upregulated in CRR cells in vitro and in a mouse xenograft model.
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Immunohistochemistry of phosphorylated Nrf2 (p-Nrf2) was performed in 110 patients with OSCC who underwent preoperative chemoradiotherapy and surgery. The effects of Nrf2 downregulation on radiosensitivity and the involvement of glycolysis in Nrf2-mediated radioresistance were evaluated. Two OSCC cell lines (SAS and HSC-2) and their clinically relevant radioresistant (CRR) clones (SAS-R, HSC-2-R) were used.
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However, little is known about the association between Nrf2 and radioresistance in OSCC. Resistance to radiotherapy is a major obstacle in treating oral squamous cell carcinoma (OSCC).
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Nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of critical antioxidant proteins, was recently demonstrated to play a key role in cancer progression.