Hypotaurine evokes a malignant phenotype in glioma through aberrant hypoxic signaling

// Peng Gao 1, 6, * , Chunzhang Yang 2, 7, * , Cody L. Nesvick 2 , Michael J. Feldman 2 , Saman Sizdahkhani 2 , Huailei Liu 3 , Huiying Chu 4 , Fengxu Yang 1, 5 , Ling Tang 1 , Jing Tian 5 , Shiguang Zhao 3 , Guohui Li 4 , John D. Heiss 2 , Yang Liu 1 , Zhengping Zhuang 2 , Guowang Xu 1 1 Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China 2 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA 3 Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China 4 Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China 5 School of Bioengineering, Dalian Polytechnic University, Dalian, China 6 Clinical Laboratory, Dalian Sixth People’s Hospital, Dalian, China 7 Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, MD, USA * These authors have contributed equally to this work Correspondence to: Zhengping Zhuang, e-mail: zhuangp@ninds.nih.gov Guowang Xu, e-mail: xugw@dicp.ac.cn Shiguang Zhao, e-mail: guangsz@hotmail.com Guohui Li, e-mail: ghli@dicp.ac.cn Keywords: hypoxia, hypoxia-inducible factors, hypotaurine, metabolomics, glioma Received: November 17, 2015     Accepted: January 31, 2016     Published: February 25, 2016 ABSTRACT Metabolomics has shown significant potential in identifying small molecules specific to tumor phenotypes. In this study we analyzed resected tissue metabolites using capillary electrophoresis-mass spectrometry and found that tissue hypotaurine levels strongly and positively correlated with glioma grade. In vitro studies were conducted to show that hypotaurine activates hypoxia signaling through the competitive inhibition of prolyl hydroxylase domain-2. This leads to the activation of hypoxia signaling as well as to the enhancement of glioma cell proliferation and invasion. In contrast, taurine, the oxidation metabolite of hypotaurine, decreased intracellular hypotaurine and resulted in glioma cell growth arrest. Lastly, a glioblastoma xenograft mice model was supplemented with taurine feed and exhibited impaired tumor growth. Taken together, these findings suggest that hypotaurine is an aberrantly produced oncometabolite, mediating tumor molecular pathophysiology and progression. The hypotaurine metabolic pathway may provide a potentially new target for glioblastoma diagnosis and therapy.