Aims Astrocytes adapt to acute acid stress. Intriguingly, cancer cells with astrocytic differentiation thrive even better in an acidic microenvironment. How changes in extracellular pH (pHe) are sensed and measured by the cell surface assemblies that first intercept the acid stress, and how this information is relayed downstream for an appropriate survival response remains largely uncharacterized. Methods In vitro cell‐based studies were combined with an in vivo animal model to delineate the machinery involved in pH microenvironment sensing and generation of mechanoadaptive responses in normal and neoplastic astrocytes. The data was further validated on patient samples from acidosis driven ischaemia and astrocytic tumour tissues. Results We demonstrate that low pHe is perceived and interpreted by cells as mechanical stress. GM3 acts as a lipid‐based pH sensor, and in low pHe, its highly protonated state generates plasma membrane deformation stress which activates the IRE1‐sXBP1‐SREBP2‐ACSS2 response axis for cholesterol biosynthesis and surface trafficking. Enhanced surface cholesterol provides mechanical tenacity and prevents acid‐mediated membrane hydrolysis, which would otherwise result in cell leakage and death. Conclusions In summary, activating these lipids or the associated downstream machinery in acidosis‐related neurodegeneration may prevent disease progression, while specifically suppressing this key mechanical ‘sense‐respond’ axis should effectively target astrocytic tumour growth.
Background Glioblastoma multiforme (GBM) is a deadly brain tumour with minimal survival rates due to the ever-expanding heterogeneity, chemo and radioresistance. Kinases are known to crucially drive GBM pathology; however, a rationale therapeutic combination that can simultaneously inhibit multiple kinases has not yet emerged successfully. Results Here, we analyzed the GBM patient data from several publicly available repositories and deduced hub GBM kinases, most of which were identified to be SUMOylated by SUMO2/3 isoforms. Not only the hub kinases but a significant proportion of GBM upregulated genes involved in proliferation, metastasis, invasion, epithelial-mesenchymal transition, stemness, DNA repair, stromal and macrophages maintenance were also identified to be the targets of SUMO2 isoform. Correlatively, high expression of SUMO2 isoform was found to be significantly associated with poor patient survival. Conclusions Although many natural products and drugs are evidenced to target general SUMOylation, however, our meta-analysis strongly calls for the need to design SUMO2/3 or even better SUMO2 specific inhibitors and also explore the SUMO2 transcription inhibitors for universally potential, physiologically non-toxic anti-GBM drug therapy. Graphical Abstract
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