Abstract
The poor prognosis of esophageal squamous cell carcinoma (ESCC) emphasizes the urgent need to better understand the carcinogenesis and develop prevention strategies. Previous studies have highlighted the potential of using Vitamin E (tocopherols) for cancer chemoprevention, but the preventive activity of α-Tocopherol against ESCC remains to be elucidated. Our data showed that early-stage supplementation with α-Tocopherol significantly prevented esophageal carcinogenesis induced by N-nitrosomethylbenzylamine (NMBA) in ESCC rat model. In the Het-1A cell model, α-Tocopherol markedly suppressed cell proliferation, promoted cell cycle G2-phase arrest and increased apoptosis. Gene microarray and proteins array analysis indicated that Akt signaling was a potential target for α-Tocopherol. We further demonstrated that α-Tocopherol increased the expression of PPARγ and its downstream tumor suppressor PTEN. Knockdown of PPARγ activated Akt signaling transduction, whereas this process was attenuated by the presence of α-Tocopherol and PPARγ agonist Rosiglitazone. In contrast, the effect of α-Tocopherol on Akt inhibition was not observed in established tumors, neither in cancerous cell lines which constitutively expressed higher levels of PPARγ. These results were closely correlated with the ineffectiveness of α-Tocopherol in the late stage of ESCC carcinogenesis. Taken together, our study suggested that α-Tocopherol may serve as a PPARγ agonist for the chemoprevention of esophageal cancer.
Highlights
Esophageal squamous cell carcinoma (ESCC), which is the predominant histopathological form of esophageal cancer, often results in poor prognosis due to the limited clinical approaches available for early diagnosis and therapeutic treatment [1, 2]
We have demonstrated that a diet that was low in α-Tocopherol and selenium enhanced Nnitrosomethylbenzylamine (NMBA)-induced esophageal carcinogenesis in rats, and this process was attenuated by dietary supplementation with α-Tocopherol and selenium [18]
These data suggest that dietary supplementation with α-Tocopherol at the early stage of esophageal squamous cell carcinoma (ESCC) can dramatically inhibit NMBA-induced esophageal carcinogenesis in rat model, and the initiation-stage intervention is more effective than the later-stage intervention
Summary
Esophageal squamous cell carcinoma (ESCC), which is the predominant histopathological form of esophageal cancer, often results in poor prognosis due to the limited clinical approaches available for early diagnosis and therapeutic treatment [1, 2]. Epidemiology studies in Linxian, an area in northern China with high incidence of ESCC, suggested that dietary deficiency of α-Tocopherol and selenium was associated with higher risk of ESCC and gastric cardia cancer [6, 7]. Some recent studies suggested that vitamin E and analog promoted lung cancer progression [14] and melanoma metastasis in mice [15]. The interpretation of these results may vary and the cancer preventive activities of tocopherols are still unclear [5, 16]
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