ADO/hypotaurine: a novel metabolic pathway contributing to glioblastoma development

Abstract

Significant advance has been made towards understanding glioblastoma metabolism through global metabolomic profiling. However, hitherto little is known about the role by which altered metabolism plays in driving the aggressive glioma phenotype. We have previously identified hypotaurine as one of the top-ranked metabolites for differentiating low- and high-grade tumors, and that there is also a strong association between the levels of intratumoral hypotaurine and expression of its biosynthetic enzyme, cysteamine (2-aminoethanethiol) dioxygenase (ADO). Using transcription profiling, we further uncovered that the ADO/hypotaurine axis targets CCL20 secretion through activating the NF-κB pathway to drive the self-renewal and maintenance of glioma ‘cancer stem cells’ or glioma cancer stem-like cells. Conversely, abrogating the ADO/hypotaurine axis using CRISPR/Cas9-mediated gene editing limited glioblastoma cell proliferation and self-renewal in vitro and tumor growth in vivo in an orthotopical mouse model, indicating that this metabolic pathway is a potential key therapeutic target. Collectively, our results unveil a targetable metabolic pathway, which contributes to the growth and progression of aggressive high-grade gliomas, as well as a novel predictive marker for glioblastoma diagnosis and therapy.

Metabolic Rewiring and the Characterization of Oncometabolites

“…A recent study was reported in which ADO was abrogated using CRISPR/Cas9-mediated gene editing. This limited the proliferation of glioblastoma cells in vitro and tumor growth in vivo in a mouse model [96]. These findings strongly support the role of hypotaurine as an oncometabolite in glioblastoma and point to potential druggable targets for this tumor.…”

Genomics-based annotations help unveil the molecular composition of edible plants

“…For example, 5-methylthioadenosine (MTA), a sulfur-containing nucleoside has recently reported as tumor suppresser 47 . Another cancer associated compound, hypotaurine, a sulfinic acid with antioxidant properties, derived from cysteine and an intermediate in taurine production, is one of the top ranked metabolites for differentiating low and high grade tumors 48 but was also shown to evoke a malignant phenotype in glioma, the most common primary brain malignancies in adults 49 . It is also marketed as a dietary supplement, together with taurine and L-carnitine and associated with semen quality improvement 50 .…”

“…The copyright holder for this preprint this version posted January 25, 2022. ; https://doi.org/10.1101/2022.01.24.477528 doi: bioRxiv preprint ranked metabolites for differentiating low and high grade tumors 48 but was also shown to evoke a malignant phenotype in glioma, the most common primary brain malignancies in adults 49 . It is also marketed as a dietary supplement, together with taurine and L-carnitine and associated with semen quality improvement 50 .…”

Glucose and Amino Acid Metabolic Dependencies Linked to Stemness and Metastasis in Different Aggressive Cancer Types

“…Taurine is an amino sulfonic acid not used for protein synthesis, but with several physiological roles as osmotic pressure controller, neuromodulator and immunomodulator ( Shen et al, 2021 ). Taurine is synthesised either from cysteine oxidation via cysteine dioxygenase, which generates cysteinesulfinate that is decarboxylated by cysteinesulfinic acid decarboxylase, or from cysteamine oxidation by cysteamine (2-aminoethanethiol) dioxygenase (ADO) ( Ueki and Stipanuk, 2009 ).…”

“…ADO expression is significantly higher in GBM when compared to lower grade gliomas and its expression is upregulated in GSCs. Moreover, ADO overexpression promotes glioma stemness via NF-κB signalling ( Shen et al, 2021 ).…”