Autocrine glutamatergic transmission for the regulation of embryonal carcinoma stem cells.
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.
Department of Pharmacology and Chemical Biology, Basic Medicine Faculty of Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Present address: Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, Hubei 443003, China.
Lin
L
Teng
Department of Pharmacology and Chemical Biology, Basic Medicine Faculty of Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Hui-Min
HM
Lei
Department of Pharmacology and Chemical Biology, Basic Medicine Faculty of Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Department of Pharmacy, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Fan
F
Sun
Department of Pharmacology and Chemical Biology, Basic Medicine Faculty of Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China.
Shi-Min
SM
An
Department of Pharmacology and Chemical Biology, Basic Medicine Faculty of Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China.
Ya-Bin
YB
Tang
Department of Pharmacology and Chemical Biology, Basic Medicine Faculty of Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Shuang
S
Meng
Department of Pharmacology and Chemical Biology, Basic Medicine Faculty of Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China.
Cong-Hui
CH
Wang
Department of Pharmacology and Chemical Biology, Basic Medicine Faculty of Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China.
Ying
Y
Shen
Department of Pharmacology and Chemical Biology, Basic Medicine Faculty of Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China.
Hong-Zhuan
HZ
Chen
Department of Pharmacology and Chemical Biology, Basic Medicine Faculty of Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China.
Liang
L
Zhu
D000818:Animals; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002853:Chromatography, Liquid; D003600:Cytosol / Q000378:metabolism; D054278:Embryonal Carcinoma Stem Cells / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018377:Neurotransmitter Agents / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D053719:Tandem Mass Spectrometry
D018377:Neurotransmitter Agents; D016194:Receptors, N-Methyl-D-Aspartate; D005973:Glutamine; D018698:Glutamic Acid
autocrine; embryonal carcinoma stem cell; glutamatergic; signaling; transmission