Tocopherols inhibit esophageal carcinogenesis through attenuating NF-κB activation and CXCR3-mediated inflammation

Esophageal cancer is one of the common causes of cancer mortality in the world. The predominant histological subtype, esophageal squamous cell carcinoma (ESCC), often results in poor prognosis due to the lack of effective approaches for the early diagnosis and treatment, highlighting the need for preventive intervention against this disease. Here we report that dietary tocopherols significantly prevents esophageal carcinogenesis by inhibiting the activation of NF-κB and the subsequent interaction of chemokine CXCL9/10/11 with their receptor CXCR3 in ESCC induced by N-nitrosomethylbenzylamine (NMBA) in murine models. Dietary supplementation with 0.15% α-tocopherol (α-T), δ-tocopherol (δ-T), or γ-tocopherol rich mixture (γ-TmT) markedly suppressed the production of pro-inflammatory cytokines, as well as the induction of CXCR3+ effector T cells (CD4+ Th1 and CD8+ CTLs) infiltration, especially at the early stage of carcinogenesis. In experiments in vivo and in vitro, these events were tightly correlated with the blockade of NF-κB activation. Our results show that tocopherols decrease carcinogenesis through inhibiting NF-κB and CXCR3 signaling, as well as related inflammation in early premalignant lesions. This pathway may offer a novel target for chemoprevention of esophageal cancer.