Selenite inhibits glutamine metabolism and induces apoptosis by regulating GLS1 protein degradation via APC/C-CDH1 pathway in colorectal cancer cells

// Junzhang Zhao 2, 3, 4, 5, * , Rui Zhou 2, 3, * , Kaiyuan Hui 4, 6 , Yang Yang 4 , QiuYue Zhang 1 , Yali Ci 4 , Lei Shi 4 , Caimin Xu 4 , Fang Huang 1 , Yu Hu 1 1 Union Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, China 2 Department of Gastroenterology, Zhongnan Hospital of Wuhan University of Medicine, Wuhan, China 3 The Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China 4 National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China 5 Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China 6 Tumor Laboratory, Department of Radiation Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, China * These authors contributed equally to this work Correspondence to: Yu Hu, email: proton948@hotmail.com Fang Huang, email: proton948@126.com Keywords: glutamnase, selenite, colorectal cancer Received: August 01, 2015 Accepted: October 21, 2016 Published: November 25, 2016 ABSTRACT Glutaminolysis is important for metabolism and biosynthesis of cancer cells, and GLS is essential in the process. Selenite is widely regarded as a chemopreventive agent against cancer risk. Emerging evidence suggests that it also has chemotherapeutic potential in various cancer types, but the mechanism remains elusive. We demonstrate for the first time that supranutritional dose of selenite suppresses glutaminolysis by promoting GLS1 protein degradation and apoptosis. Mechanistically, selenite promotes association of APC/C-CDH1 with GLS1 and leads to GLS1 degradation by ubiquitination, this process is related to induction of PTEN expression. In addition, GLS1 expression is increased in human colorectal cancer tissues compared with normal mucosae. Our data provide a novel mechanistic explanation for the anti-cancer effect of selenite from a perspective of cell metabolism. Moreover, our results indicate that glutaminolysis especially GLS1 could be an attractive therapeutic target in colorectal cancer.