Abstract
Aldehyde dehydrogenase 1 isoforms A1 and A3 have been implicated as functional biomarkers associated with distinct molecular subtypes of glioblastoma and glioblastoma stem cells. However, the exact roles of these isoforms in different types of glioma cells remain unclear. The purpose of this study was to dissect the association of A1 or A3 isoforms with stem and non-stem glioblastoma cells. This study has undertaken a systematic characterization of A1 and A3 proteins in glioblastoma tissues and a panel of glioblastoma stem cells using immunocytochemical and immunofluorescence staining, Western blot and the subcellular fractionation methodology. Our main findings are (i) human GSCs express uniformly ALDH1A3 but not the ALDH1A1 isoform whereas non-stem glioma cells comparably express both isoforms; (ii) there is an abundance of ALDH1A3 peptides that prevail over the full-length form in glioblastoma stem cells but not in non-stem glioma cells; (iii) full-length ALDH1A3 and ALDH1A3 peptides are spatially segregated within the cell; and (vi) the abundance of full-length ALDH1A3 and ALDH1A3 peptides is sensitive to MG132-mediated proteasomal inhibition. Our study further supports the association of ALDH1A3 with glioblastoma stem cells and provide evidence for the regulation of ALDH1A3 activities at the level of protein turnover.
Highlights
Previous investigations of aldehyde dehydrogenase 1 (ALDH1) isoforms in GB have relied on expression patterns identified by using non-selective antibodies that recognize both ALDH1A1 and ALDH1A3 isoforms
IHC assessments of ten GBs reveal heterogeneous patterns characterized by either segregated or concomitant expression of ALDH1A1 and ALDH1A3 in GB cells (Figure 1, data shown for five representative tumors)
ALDH1A3 turnover is regulated by the ubiquitin-proteasome system [21], we considered the possibility possibility that degradation
Summary
Our study further supports the association of ALDH1A3 with glioblastoma stem cells and provide evidence for the regulation of ALDH1A3 activities at the level of protein turnover. The current biological paradigm for GB is centered on so-called glioma stem cells (GSCs), implicated as the most tumorigenic type of glioma cells responsible for GB initiation and progression, before and after cytotoxic therapy [4]. Owing to their inherent plasticity, GSCs are capable of adapting to non-targeted therapies, defining them as the most clinically relevant target cell in GB [5].
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