RESPONSIVENESS OF STEM-LIKE HUMAN GLIOMA CELLS TO ALL-TRANS RETINOIC ACID AND REQUIREMENT OF RETINOIC ACID RECEPTOR ISOTYPES α, β AND γ

Retinoic acid (RA) is required for development and homeostasis of the normal mammalian brain and may play a role in the initiation and progression of malignant brain tumors, such as the glioblastoma multiforme (GBM) and the gliosarcoma (Gsarc). The subpopulation of stem-like glioma cells (SLGCs) was shown to resist standard glioma radio-/chemotherapy and to propagate tumor regrowth. We used phenotypically distinct, self-renewing SLGC lines from six human GBMs, two Gsarcs, and two subcloned SLGC derivatives in order to investigate their responsiveness to all-trans retinoic acid (atRA) and to identify the RA-receptor (RAR) isotypes involved. In general, atRA exerted a pro-proliferative and pro-survival effect on SLGCs, though the efficacy was distinct. By means of RAR isotype-selective retinoids we disclosed that these effects were mediated by RAR alpha and RAR gamma, except for one SLGC line, in which the pro-proliferative signal was induced by the RAR beta-selective retinoid. Only one GBM-derived cell line (T1338) and a subpopulation of another (T1389) displayed neural differentiation in response to atRA. Differentiation of T1338 was induced by RAR alpha and RAR gamma isotype-selective retinoids, associated with down-regulation of Sox2, and the failure to induce orthotopic tumors in the brains of SCID mice. The differential responsiveness of the SLGC lines appeared unrelated to the expression of RAR beta, as (i) atRA augmented RAR isotype mRNA expression and particularly rar beta mRNA in all SLGC lines, (ii) rar beta promoter hypomethylation in the SLGC lines was not related to differentiation and (iii) the induction of T1338 differentiation was by RAR alpha- and RAR gamma-selective ligands. (c) 2014 IBRO. Published by Elsevier Ltd. All rights reserved.