Association between cytoplasmic CRABP2, altered retinoic acid signaling, and poor prognosis in glioblastoma

Abstract

Retinoic acid (RA), a metabolite of vitamin A, is required for the regulation of growth and development. Aberrant expression of molecules involved in RA signaling has been reported in various cancer types including glioblastoma multiforme (GBM). Cellular retinoic acid-binding protein 2 (CRABP2) has previously been shown to play a key role in the transport of RA to retinoic acid receptors (RARs) to activate their transcription regulatory activity. Here, we demonstrate that CRABP2 is predominantly located in the cytoplasm of GBM tumors. Cytoplasmic, but not nuclear, CRABP2 levels in GBM tumors are associated with poor patient survival. Treatment of malignant glioma cell lines with RA results in a dose-dependent increase in accumulation of CRABP2 in the cytoplasm. CRABP2 knockdown reduces proliferation rates of malignant glioma cells, and enhances RA-induced RAR activation. Levels of CRYAB, a small heat shock protein with anti-apoptotic activity, and GFAP, an astrocyte-specific intermediate filament protein, are greatly reduced in CRABP2-depleted cells. Restoration of CRYAB expression partially but significantly reversed the effect of CRABP2 depletion on RAR activation. Our combined in vivo and in vitro data indicate that: (i) CRABP2 is an important determinant of clinical outcome in GBM patients, and (ii) the mechanism of action of CRABP2 in GBM involves sequestration of RA in the cytoplasm and activation of an anti-apoptotic pathway, thereby enhancing proliferation and preventing RA-mediated cell death and differentiation. We propose that reducing CRABP2 levels may enhance the therapeutic index of RA in GBM patients.

Differential CRABP-II and FABP5 expression patterns and implications for medulloblastoma retinoic acid sensitivity

“…It has been proposed that CRABP-II and FABP5 are signicant prognostic factors associated with poor survival in certain cancers such as glioblastoma and breast cancer. 32,33 Our results show that the expression levels of CRABP-II and FABP5, in both classic and large-cell MBs, were signicantly higher than those in nodular MBs. Due to the classic and large-cell histological subtypes presenting worse clinical outcomes than the nodular subtype, up-regulated CRABP-II and FABP5 may be related to prognosis in MB patients.…”

A novel functional polymorphism of GFAP decrease glioblastoma susceptibility through inhibiting the binding of miR-139

“…The potential molecular mechanism of GFAP promoting the aggressiveness of GBM is also important. Liu et al revealed that retinoic acid (RA) and its derivatives, initiate RA-linked signaling transductions and induce chemotherapy sensitivity in GBM [ 15 ]. Moreover, changes of cellular RA balance in GBM might also be related to changes of GFAP expression and phenotypes.…”

ω-3 and ω-6 Fatty Acids Modulate Conventional and Atypical Protein Kinase C Activities in a Brain Fatty Acid Binding Protein Dependent Manner in Glioblastoma Multiforme

“…Semiquantitative RT-PCR was used to verify differential expression of selected PKCs in U87 control and B-FABP-transfected cells as well as in GBM cell lines that are either negative (T98, U87, A172, CLA, and M021) or positive (U251, U373, M049, M103, and M016) for B-FABP [ 12 , 31 , 32 ]. Sources of GBM cell lines have been described previously [ 33 ] and they are as follows: T98, from Walter Nelson-Rees, Naval Biomedical Research Station, Oakland, CA, USA; U87, U251, and U373, from Jorgen Fogh, Sloane Kettering Institute, Rye, NY, USA; A172, from Stuart A. Aaronson, NCI, Bethesda, MD, USA; CLA, from Paul Kornblith, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA. M016, M021, M049, and M103 GBM cell lines were obtained from Drs.…”