Abstract
Glioblastomas respond differently to all-trans retinoic acid (RA) for unknown reasons. Because CRABP-II and FABP5 mediate RA intracellular signaling respectively and lead to distinct biological consequences, their expression patterns in different grades of astrocytomas and the glioblastoma cells lines LN18, LN428 and U251 were examined to identify potential correlations with RA sensitivities. The response of glioblastoma cells to RA, decitabine or the FABP5 competitive inhibitor, BMS309403, was analyzed. CRABP-II and FABP5 were expressed to varying degrees by the 84-astrocytoma cases examined. Treatment of LN428, U251 and LN18 cells with RA failed to suppress their growth; however, U251 proliferation was inhibited by decitabine. The combination of decitabine and RA suppressed the growth of all three cell lines and induced significant apoptosis of LN428 and U251 cells. Both CRABP-II and FABP5 were transcribed in the three cell lines but FABP5 proteins were undetectable in U251 cells. The ratio of CRABP-II to FABP5 was not altered after RA, decitabine or RA and decitabine treatment and the resistance of cells to RA was not reversed by BMS309403 treatment. In conclusion, CRABP-II and FABP5 expression patterns are neither related to the tumor grades nor correlated with RA sensitivity. Additional molecular factors may be present that determines the sensitivity of glioblastoma cells to RA. Dicitabine may improve the sensitivity of glioblastoma cells to RA, however, its underlying mechanism and its in vivo feasibility need to be investigated.
Highlights
Glioblastoma multiforme (GBM) is the most aggressive and common brain malignancy in adults [1]
A total of 84 astrocytoma specimens were classified into Grade I, II, III or IV according to the criteria of World Health Organization classification system [1] (Table 1)
The surrounding tissues were positive for CRABP-II but negative for FABP5 (Figure 1A)
Summary
Glioblastoma multiforme (GBM) is the most aggressive and common brain malignancy in adults [1]. RA is able to inhibit the growth of promyelocytes and medulloblastoma cells by promoting their differentiation and apoptosis [13, 14]. In other cancers, RA appears to promote rather than inhibit cell survival. RA can promote cell survival and growth of NaF mammary tumor cells of the MMTVneu mouse [15] and enhance skin tumor formation [16]. Some studies have demonstrated a therapeutic benefit of RA in the treatment of human glioblastomas [17], whereas, other studies found www.impactjournals.com/oncotarget that retinoids failed to inhibit proliferation and migration of human glioblastoma cells [18]. RA has been demonstrated to enhance the transcription of a group of cancer-associated genes in glioblastoma cells [19]. The cause of different RA sensitivities in glioblastoma cells is unknown
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