Article
Retinoid resistance and multifaceted impairment of retinoic acid synthesis in glioblastoma
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Published: | May 13, 2014 |
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Objective: Measuring concentrations of the differentiation-promoting hormone retinoic acid (RA) in glioblastoma tissues would reveal why RA treatment of brain tumor patients is inefficient.
Method: We apply a HPLC-based extraction and measurement protocol to screen glioblastoma tissues for levels of the RA precursor retinol and biologically active RA. We combine this approach with mRNA analyses of 27 tumors and 6 normal brains as well as with methylation and ChiP analyses of gliobalstoma cell cultures.
Results: We report impaired RA synthesis in a large fraction of glioblastomas. Low RA in tumors stems from the reduced conversion of the RA precursor retinol and is linked to a repression of RA-synthesizing enzymes ALDH1A1, ALDH1A2 and ALDH1A3 through epigenetic silencing and chromosomal deletions. Intriguingly, chromatin at RA target genes is poised to RA substitution, but most glioblastoma cell cultures are completely resistant to RA treatment. Through in vitro studies we show that this paradoxic RA response is unrelated to alternative RA signaling through the FABP5/PPARD axis. Instead, we link RA resistance to the activation of AKT as well as to the inactivation of the pro-apoptotic downstream targets BAD and GSKß3.
Conclusions: Our data uncover a multifaceted disturbance of the RA synthesis in glioblastomas and suggest a fresh look at current RA treatment strategies.