title: The transient receptor potential vanilloid-2 cation channel impairs glioblastoma stem-like cell proliferation and promotes differentiation.
abstract: Malignant transformation of cells resulting from enhanced proliferation and aberrant differentiation is often accompanied by changes in transient receptor potential vanilloid (TRPV) channels expression. In gliomas, recent evidence indicates that TRPV type 2 (TRPV2) negatively controls glioma cell survival and proliferation. In addition, cannabinoids, the ligands of both cannabinoid and TRPV2 receptors, promote glioblastoma stem-like cells (GSCs) differentiation and inhibit gliomagenesis. Herein, we provide evidence on the expression of TRPV2 in human GSCs and that GSCs differentiation reduces nestin and progressively increases both the glial fibrillary acidic protein (GFAP) and TRPV2 expression. Therefore, we evaluated the role of TRPV2 cation channel in GSC lines differentiation. Treatment of GSC lines with the TRPV antagonist Ruthenium Red, with ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid or knockdown of TRPV2 gene during differentiation, decreases GFAP and class III beta-tubulin (β(III)-tubulin) expression; conversely, phorbol-12-myristate-13-acetate stimulates GSCs proliferation, reduces TRPV2 expression and partially reverts astroglial differentiation. In addition, forced TRPV2 expression in GSC lines by stable TRPV2 transfection increases GFAP and β(III)-tubulin expression and parallelly reduces proliferation. Finally, TRPV2 overexpression inhibits GSCs proliferation in a xenograft mouse model, as shown by reduced tumor diameter and mitotic index, and promotes the differentiation of GSCs toward a more mature glial phenotype. Overall, our results demonstrate that TRPV2 promotes in vitro and in vivo GSCs differentiation and inhibits their proliferation. Better understanding of the molecular mechanisms that regulate the balance between proliferation and differentiation of GSCs would lead to more specific and efficacious pharmacological approaches.
authors.affiliation: Section of Experimental Medicine, School of Pharmacy, University of Camerino, Camerino, Italy.
authors.forename: Maria Beatrice
authors.initials: MB
authors.lastname: Morelli
authors.forename: Massimo
authors.initials: M
authors.lastname: Nabissi
authors.forename: Consuelo
authors.initials: C
authors.lastname: Amantini
authors.forename: Valerio
authors.initials: V
authors.lastname: Farfariello
authors.forename: Lucia
authors.initials: L
authors.lastname: Ricci-Vitiani
authors.forename: Simona
authors.initials: S
authors.lastname: di Martino
authors.forename: Roberto
authors.initials: R
authors.lastname: Pallini
authors.forename: Luigi Maria
authors.initials: LM
authors.lastname: Larocca
authors.forename: Sara
authors.initials: S
authors.lastname: Caprodossi
authors.forename: Matteo
authors.initials: M
authors.lastname: Santoni
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.forename: Giorgio
authors.initials: G
authors.lastname: Santoni
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015870:Gene Expression; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000235:genetics*
chemical_list: D010703:Phorbol Esters; D050916:TRPV Cation Channels; C400769:TRPV2 protein, human; C119222:phorbol-12-myristate; D002118:Calcium