mGlu3 receptor blockade inhibits proliferation and promotes astrocytic phenotype in glioma stem cells.
We have characterised, using both in vivo and in vitro methods, the effects of the metabotropic glutamate receptor subtype 3 (mGlu3) antagonist (LY341495) and agonist (LY379268) on the proliferation and differentiation of glioma stem cells (GSC). For in vitro studies, a CCK-8 assay was used to determine the cell proliferation, flow cytometry was performed to determine cell cycle phases, and immunohistochemistry and laser confocal microscopy were employed to detect CD133 expression. For in vivo studies, GSCs were injected into nude mice treated with either LY379268 or LY341495 and the growth of the tumours was measured after 3 weeks. When compared with controls, the proliferation rates and proportion of cells in S phase within the LY341495 treated group decreased in a time-dependent manner. In the presence of differentiation medium containing LY341495, GSC differentiation was diverted into an astrocyte rather than neuronal phenotype. The growth rate and volume of tumours injected into nude mice was reduced in LY341495 treated mice compared with controls. Thus pharmacological blockade of mGlu3 receptor signalling pathway significantly inhibits the growth and proliferation of GSCs both in vitro and in vivo while promoting differentiation to astrocytes. These results further implicate mGlu3 in the biology of glioma and as a target for continued research.
Department of Emergency, Xinqiao Hospital, Chongqing, 400037, China.
Kun
K
Zhou
Yechun
Y
Song
Wei
W
Zhou
Chunqing
C
Zhang
Haifeng
H
Shu
Hui
H
Yang
Bin
B
Wang
D000071916:AC133 Antigen; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014966:Xanthenes / Q000494:pharmacology
D000071916:AC133 Antigen; D000596:Amino Acids; D015703:Antigens, CD; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006023:Glycoproteins; C114624:LY 341495; C118218:LY 379268; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; D014966:Xanthenes; C102718:metabotropic glutamate receptor 3; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor
differentiation; human glioma stem cells; metabotropic glutamate receptor; proliferation