Dying endothelial cells stimulate proliferation of malignant glioma cells via a caspase 3-mediated pathway

Emerging evidence has indicated that apoptotic cells have a compensatory effect on the proliferation of neighboring cells. However, the potential role of dying vascular endothelial cells (ECs) in glioma tumor proliferation remains unclear. In the present study, three glioma cell lines were cocultured with dying ECs under various conditions to evaluate the effect of dying ECs on tumor proliferation using alamarBlue and trypan blue assays to assess cell proliferation and viability, respectively. The results suggested that dying ECs had a marked ability to facilitate glioma cell growth via a caspase 3-mediated pathway. Furthermore, calcium-independent phospholipase A₂ (iPLA₂), a downstream gene regulated by caspase 3, is highly involved in this process. Prostaglandin E₂ (PGE₂) was the final effector of the caspase 3-iPLA₂ signaling pathway in glioma cell proliferation. Knockdown of caspase 3 or iPLA₂ using shRNA negated the growth stimulating effect of dying ECs. By contrast, the overexpression of iPLA₂ in ECs via the pLEX lentiviral vector system or addition of PGE₂ into culture medium had a growth promoting effect on glioma cells. Overall, the present data revealed a paracrine signal released from dying ECs which promotes the proliferation of surrounding glioma cells, demonstrating the importance of blocking compensatory proliferation during tumor therapy. Additionally, targeting caspase 3-mediated pathways combined with current therapeutic strategies may be a promising approach for improving the dismal prognosis associated with these malignant tumors.