Gliomas and Aldehyde Dehydrogenase Aldehyde dehydrogenases A
Gliomas and Aldehyde Dehydrogenase
Aldehyde dehydrogenases (ALDHs) are key metabolic enzymes involved in regulation of glycolysis/gluconeogenesis pathways as well as in the detoxification of endogenous and exogenous aldehydes, regulating cell function and homeostasis. ALDHs play important roles in cell proliferation, differentiation, and survival and comprise a family of 19 members (Table 1), which are normally involved in the biosynthesis of retinoic nvp-aew541 (RA) and folate as well as in the formation of the neurotransmitter γ-aminobutyric acid (GABA; Box 1). Selective ALDH isoenzyme activity has been detected in cancer cells with increased aggressiveness, capacity for sustained proliferation, and tumor plasticity . In addition, the ALDH isoenzymes are considered as functional biomarkers of CSCs, possessing an important mechanistic role in the metastatic activity of tumor cells as well as in modulating their response to therapy.
Role of ALDH Isoenzymes in Glioma Growth and Invasion ALDH family genes are commonly upregulated in gliomas, indicating ALDH-dependent cell metabolism. Specific ALDH isoenzymes have been detected in high- and low-grade tumors implicated in cell proliferation, maintenance of CSC properties, invasiveness, and patient survival. ALDH1A3 is the best-studied isoform, being significantly overexpressed in high-grade gliomas (HGGs) compared with low-grade gliomas. ALDH1A3 activity has been associated with cell proliferation, extracellular matrix (ECM) organization, cell adhesion, and ECM–receptor interaction . Moreover, ALDH1A3 levels are positively correlated with the expression of molecules involved in invasiveness including SNAIL, SLUG, MMP2, and MMP9. Recent genome-wide transcriptional profiling of HGGs revealed high ALDH1A3 expression exclusively in the mesenchymal (MES) subtype of CSCs but not in proneural (PN) or classical subtypes , being associated with higher mortality in survival analysis and potential clinical prognostic value. ALDH1A3 activity and glycolytic capacity were enhanced in MES CSCs compared with PN CSCs and these were strongly associated with tumor cell invasion. Pharmacological inhibition of ALDH1A3 by N,N-diethylaminoazobenzene (DEAB) or knockdown by short hairpin RNA (shRNA) specifically decreased MES CSCs number, their invasive potential, and radioresistance, suggesting ALDH1A3 as a selective biomarker for MES CSCs. In accordance, increased numbers of ALDH1A3+ cells detected in glial tumors indicative of activated cell metabolism showed an association with glioma malignancy and poor patient survival . Studies in the established glioma neurosphere line MES83 expressing high ALDH levels (ALDHhigh) revealed that ALDH1A3 upregulation was induced by the activation of the forkhead family member of transcription factors, FOXD1. Both FOXD1 and ALDH1A3 were essential for maintenance of the MES phenotype in CSCs . Furthermore, HGG analysis showed a strong association of high ALDH1A3 levels with shorter postsurgical patient survival compared with low or intermediate levels . Low ALDH1A3 expression in glioblastomas (GBMs) due to promoter hypermethylation has been linked to a better prognosis . ALDH1A1 isoform expression has also been detected in gliomas, being correlated with histological grade, proliferation, colony formation, and invasiveness . ALDH1A1 expression was elevated in CSCs of human GBM cell lines, coexpressed with other CSC markers Musashi-1 and Sox-2, and it was proportional to neurosphere formation, an independent predictor of rapid glioma tumor progression. Upon inhibition of ALDH1A1 by DEAB, RA, or both, a significant reduction in spheroid size and number was observed. In addition, ALDH1A1 inhibition induced β-III-tubulin expression – a neurospecific marker involved in the differentiation process – and decreased colony formation, indicating the contribution of ALDH1A1 to the maintenance of the undifferentiated phenotype and clonogenic capacity of CSCs. Moreover, elevated ALDH1A1 expression was detected in primary GBM cells cultured under hypoxic conditions and was implicated as a cancer self-protection property. Although high ALDH1A1 expression has been proposed as a biomarker for the prediction of survival and the molecular classification of GBM, the effects of ALDH1A1 levels in clinical outcome are controversial, being associated with both better and worse patient survival 1, 5, 6.