Autocrine glutamatergic transmission for the regulation of embryonal carcinoma stem cells
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Lin Teng1,4,*, Hui-Min Lei1,*, Fan Sun1,3, Shi-Min An1,2, Ya-Bin Tang1,2, Shuang Meng1, Cong-Hui Wang1,2, Ying Shen1,2, Hong-Zhuan Chen1,2, Liang Zhu1,2
1Department of Pharmacology and Chemical Biology, Basic Medicine Faculty of Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
2Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China
3Department of Pharmacy, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
4Present address: Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, Hubei 443003, China
*These authors have contributed equally to the work
Liang Zhu, email: [email protected]
Hong-Zhuan Chen, email: [email protected]
Keywords: autocrine, glutamatergic, signaling, embryonal carcinoma stem cell, transmission
Received: November 04, 2015 Accepted: May 30, 2016 Published: June 13, 2016
Glutamate behaves as the principal excitatory neurotransmitter in the vertebrate central nervous system and recently demonstrates intercellular signaling activities in periphery cancer cells. How the glutamatergic transmission is organized and operated in cancer stem cells remains undefined. We have identified a glutamatergic transmission circuit in embryonal carcinoma stem cells. The circuit is organized and operated in an autocrine mechanism and suppresses the cell proliferation and motility. Biological analyses determined a repertoire of glutamatergic transmission components, glutaminase, vesicular glutamate transporter, glutamate NMDA receptor, and cell membrane excitatory amino-acid transporter, for glutamate biosynthesis, package for secretion, reaction, and reuptake in mouse and human embryonal carcinoma stem cells. The glutamatergic components were also identified in mouse transplanted teratocarcinoma and in human primary teratocarcinoma tissues. Released glutamate acting as the signal was directly quantified by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Genetic and pharmacological abolishment of the endogenously released glutamate-induced tonic activation of the NMDA receptors increased the cell proliferation and motility. The finding suggests that embryonal carcinoma stem cells can be actively regulated by establishing a glutamatergic autocrine/paracrine niche via releasing and responding to the transmitter.
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