Pro-tumoral Ca 2+ signaling is dependent on Ca-α1T and Slowpoke channels in Drosophila melanogaster glioma
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Background
Ion channel-mediated cytosolic Ca 2+ oscillations play a crucial role in promoting the growth of glioblastoma, a tumor of poor prognosis. Here, we have studied the roles of Ca-α1T and Slowpoke ion channels in a Drosophila melanogaster glioblastoma model. Although their mammalian orthologs have been implicated in glioblastoma cell viability in vitro , their oncogenic potential remains uncharacterized in a complex in vivo context.
Results
We show that glial-specific RNAi targeting Ca-α1T and Slowpoke in gliomas reduces glioma cell number and membrane extension and decreases glioma cell Ca²⁺ activity and downstream activation of PI3K and pRIII/pERK signaling. Moreover, Slowpoke knockdown significantly extends glioma fly survival to near-control values and improves glioma-associated neurodegeneration. RNAseq transcriptomic analysis reveals shared regulation by both channels of pathways involved in metabolic rewiring, cell adhesion and excitatory neurotransmission, while uncovering distinct effects on synaptic function.
Conclusions
Both Ca-α1T and Slowpoke are essential for pro-tumorigenic Ca²⁺-dependent signaling in Drosophila gliomas. Common effects observed upon gene knockdown support a coordinated function for these channels at the plasma membrane. Nevertheless, their distinct impacts on survival and gene expression profiles highlight non-redundant roles. Notably, Slowpoke knockdown promotes increased survival and neuroprotection, associated with the repression of synaptic genes aberrantly upregulated in gliomas, thereby identifying Slowpoke as a promising therapeutic target in glioblastoma.
