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 0 ,N 0 -tetraacetic acid or knockdown of TRPV2 gene during differentiation, decreases GFAP and class III beta-tubulin (b 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 b 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.Malignant gliomas remain the most deadly human brain tumors with a poor prognosis despite years of research in antitumoral therapeutic strategies. A hallmark characteristic of gliomas is their molecular and cellular heterogeneity that is considered to be one of the reasons for their high malignancy and recurrence. 1,2 Neoplastic transformation of differentiated glial cells was for many years the most accepted hypothesis to explain the origin of gliomas 1,2 ; however, recent findings support the existence of a stem cell-derived origin for different types of cancers including brain tumors. 2,3 In particular,

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…In U87MG glioma cells (a human primary GBM cell line), silencing of TRPV2 by siRNA promotes growth by stimulating cell cycle (upregulated cyclin E1 and CDK2 and overexpressed Raf-1 and BCL-XL) and protecting tumor cells from apoptosis (via down-regulation of Fas/CD95 and caspase-8 expression) (Nabissi et al, 2010). In keeping with these in vitro findings, TRPV2 siRNA accelerated GBM progression in a mouse xenograft model (Morelli et al, 2012). Importantly, the reserve is also true: 1) overexpression of TRPV2 in glioma cells decreases viability by increasing proapoptotic Fas/CD95 expression, and 2) reduces the tumor volume and mitotic rate when GBM is xenografted into nude mice.…”

“…When transplanted into nude mice, the growth of the xenograft is inhibited by knockdown of the Trpv2 gene. By contrast, TRPV2 is highly expressed in normal, but not in neoplastic (glioblastoma), brain tissue (Morelli et al, 2012). Overexpression of TRPV2 inhibits glioblastoma growth in a mouse xenograft model and promotes differentiation toward a more mature glial phenotype (Morelli et al, 2012;Nabissi et al, 2013).…”

“…By contrast, TRPV2 is highly expressed in normal, but not in neoplastic (glioblastoma), brain tissue (Morelli et al, 2012). Overexpression of TRPV2 inhibits glioblastoma growth in a mouse xenograft model and promotes differentiation toward a more mature glial phenotype (Morelli et al, 2012;Nabissi et al, 2013). In other words, TRPV2 may function as an oncogene in the prostate and a tumor suppressor gene in the brain.…”

Protein interaction network (PIN)-based breast cancer subsystem identification and activation measurement for prognostic modeling

“…KaplanMeier plots shows discrimination power of the other 9 subsystems in Figure S5. Previously, up-regulation of TRPV2 was shown to be crucial to the induction of apoptotic cell death in bladder cancer [54,55,56]. Those TRP genes would be the candidates of survival outcome determinant of breast cancer, which corresponds to the implications from previous studies [57,58,59].…”

Targeting glioblastoma cancer stem cells: the next great hope?

“…Other differentiating targets include girdin (an actin-binding protein) 97 and the vanilloid-2 cation channel. 94 Cannabinoids and sorafenib have also been documented to induce glioma CSC differentiation and deplete the CSC population. …”