Cyclic AMP Signaling in Glioma Biology

Cyclic adenosine monophosphate (cAMP) serves as a pivotal second messenger in the regulation of cellular processes that underlie glioma initiation, progression and therapeutic resistance. In healthy glial lineages, fluctuations of cAMP levels orchestrate proliferation, differentiation and programmed cell death chiefly through activation of protein kinase A (PKA) and exchange proteins directly activated by cAMP (Epac). In the context of glioma, altered expression or activity of adenylate cyclases, phosphodiesterases and G-protein-coupled receptors remodels cAMP microdomains, leading to aberrant PKA signalling and downstream effects on transcription factors such as CREB, as well as on epigenetic modifiers. Depending on cellular context, elevated cAMP can induce neuronal or glial differentiation of malignant cells, trigger mitochondrial-dependent apoptosis or inhibit invasive phenotypes. Recent advances have highlighted roles for cAMP-mediated modulation of histone acetylation and feedback loops involving β-catenin that limit differentiation. Therapeutic strategies aimed at restoring or augmenting cAMP signalling—through selective agonists, inhibitors of cAMP breakdown or epigenetic co-regulators—promise to reprogramme tumour cells towards less aggressive states, sensitise glioma stem cells to standard treatments and expand the repertoire of differentiation-based interventions.

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Cyclic AMP Signaling in Glioma Biology publication trend

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Technical terms

cyclic AMP (cAMP): A diffusible intracellular messenger synthesised from ATP by adenylate cyclases that regulates diverse signalling cascades.

Protein kinase A (PKA): A holoenzyme activated by cAMP binding to its regulatory subunits, which phosphorylates protein targets to modulate cellular responses.

glioma stem cells (GSCs): A subpopulation of tumour cells with self-renewal capacity and resistance to therapy, thought to drive glioma recurrence.

histone acetylation: A chromatin modification in which acetyl groups are added to lysine residues on histone proteins, generally promoting gene transcription.

β-catenin pathway: A signalling cascade in which β-catenin translocates to the nucleus to regulate genes involved in proliferation and differentiation.

References

1. Differential regulation of H3K9/H3K14 acetylation by small molecules drives neuron-fate-induction of glioma cell. Cell Death & Disease (2023).
2. Disruption of β-catenin-mediated negative feedback reinforces cAMP-induced neuronal differentiation in glioma stem cells. Cell Death & Disease (2022).
3. MOB2 suppresses GBM cell migration and invasion via regulation of FAK/Akt and cAMP/PKA signaling. Cell Death & Disease (2020).