Research Papers:
Selenite inhibits glutamine metabolism and induces apoptosis by regulating GLS1 protein degradation via APC/C-CDH1 pathway in colorectal cancer cells
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Abstract
Junzhang Zhao2,3,4,5,*, Rui Zhou2,3,*, Kaiyuan Hui4,6, Yang Yang4, QiuYue Zhang1, Yali Ci4, Lei Shi4, Caimin Xu4, Fang Huang1, Yu Hu1
1Union Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, China
2Department of Gastroenterology, Zhongnan Hospital of Wuhan University of Medicine, Wuhan, China
3The Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, China
4National 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
5Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
6Tumor 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: [email protected]
Fang Huang, email: [email protected]
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.
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