Abstract
Abstract Background: Cancer cells consume large amount of energy and maintain high levels of anabolism to promote cell proliferation via metabolic reprogramming. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master transcription regulator of stress and promotes metabolic reprogramming to support cell proliferation in various type of cancers. In particular, esophageal cancer was regarded as one of the most aggressive tumors of gastrointestinal cancer. However, the effect of metabolic reprogramming in esophageal cancer tissues was not fully understood. In this study, we investigated the prognostic significance of Nrf2, impacts on metabolic reprogramming and reactive oxygen species (ROS) detoxification in esophageal cancer. Methods: We immunohistochemically evaluated the protein expression of Nrf2 in the surgically resected specimens in 201 esophageal cancer patients. By using esophageal cancer cell lines, we examined the change of phenotype and the regulation of ROS, compared control cells with Nrf2 depletion cells. Moreover, we measured the levels of metabolites in the esophageal cancer cell lines by using mass spectrometry and identified the metabolic pathway Nrf2 promoted. Results: We revealed that high expression of Nrf2 in esophageal cancer was associated with tumor recurrence (P=0.0004) and poor prognosis (P<0.0001) by immunohistochemical analysis using resected specimen. In TE-11, the esophageal cancer cell line with high expression of Nrf2, depletion of Nrf2 dramatically decreased cell growth and enhanced G1 cell cycle arrest and apoptosis in vitro assay. In that situation, we showed that ROS which was not removed by Nrf2 detoxification activated p38 mitogen activated protein kinase (MAPK) pathway and promoted G1 cell cycle arrest and apoptosis. Furthermore, metabolome analysis compared control cells with Nrf2 depleted cells showed that Nrf2 can strongly promoted metabolic reprogramming to glutathione metabolism, which synthesized the essential fuels for cancer progression. The mechanism Nrf2 promoted glutathione metabolism was that Nrf2 regulated the levels of main enzymes (GCLM, GCLC, and xCT) catalyzing glutathione synthesis. Conclusions: The expression of Nrf2 was up-regulated in some esophageal cancer cell lines and resected tumor specimen. And, high expression of Nrf2 in esophageal cancer was associated with poor prognosis. Our in vitro assay revealed that Nrf2 appeared to promote esophageal cancer cell proliferation via metabolic reprogramming and ROS detoxification. Therefore, strategies to pharmacologically manipulate the level and / or activity of Nrf2 may have potential to reduce tumor growth and improve the prognosis of esophageal cancer patients. Citation Format: Yuki Kitano, Yoshifumi Baba, Shigeki Nakagawa, Kosuke Mima, Hiroshi Sawayama, Masaaki Iwatsuki, Yasuo Sakamoto, Yo-ichi Yamashita, Naoya Yoshida, Hideo Baba. Nrf2 promotes esophageal cancer cell proliferation via metabolic reprogramming and ROS detoxification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3556. doi:10.1158/1538-7445.AM2017-3556
Published Version
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