Alpha-Tocopherol prevents esophageal squamous cell carcinoma by modulating PPARγ-Akt signaling pathway at the early stage of carcinogenesis
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Miao Xu1,*, Hui Yang2,*, Qiannan Zhang2, Ping Lu3, Yongquan Feng2, Xue Geng2, Lishi Zhang1 and Xudong Jia2
1West China School of Public Health, Sichuan University, Chengdu, China
2Key Laboratory of Food Safety Risk Assessment of Ministry of Health, National Center for Food Safety Risk Assessment, Beijing, China
3Beijing University of Agriculture, Beijing, China
*The authors have contributed equally to this work
Xudong Jia, email: [email protected]
Lishi Zhang, email: [email protected]
Keywords: vitamin E; tocopherol; esophageal cancer; Akt; PPARγ
Received: June 09, 2017 Accepted: August 17, 2017 Published: September 30, 2017
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.
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