Abstract
Malignant glioma is one of the most common and deadly tumors in the central nervous system while developing effective treatments for this devastating disease remains a challenge. Previously, we demonstrated that the vitamin nicotinic acid (NA) inhibits glioma invasion. Here, we show that high-dose NA induces apoptosis of malignant glioma cells in vitro and in vivo. In cultured U251 glioma cells treated with NA, we detected ER stress that was likely caused by elevated intracellular calcium levels. The elevated calcium can be attributed to the activation of TRPV1, a cation channel that has been implicated in cutaneous flushing caused by NA administration. Our data further suggested that NA-induced apoptosis is mediated by the calcium-dependent proteases called calpains, whose activities are drastically upregulated by NA. NA-induced apoptosis of U251 cells can be attenuated by blocking calpain activity or knocking down TRPV1. These results reveal a novel function of NA in regulating glioma cell apoptosis via the calcium-dependent ER stress pathway and imply a potential application of NA for the treatment of malignant glioma.
Highlights
Glioma, which accounts for nearly 30% of all primary brain tumors, is one of the most challenging solid tumors to treat in the central nervous system (Weller et al, 2015)
High-dose nicotinic acid (NA) induces apoptosis of glioma cells in vitro and in vivo We previously demonstrated that 7.0 mM NA inhibits glioma invasion by facilitating Snail1 degradation (Li et al, 2017)
We showed that NA modulates intracellular calcium concentration in NIH3T3 cells and inhibits the invasion of glioma cells by promoting Snail1 degradation (Li et al, 2014; Li et al, 2017)
Summary
Glioma, which accounts for nearly 30% of all primary brain tumors, is one of the most challenging solid tumors to treat in the central nervous system (Weller et al, 2015). Gliomas are classified into pathological grades I–IV (Rasmussen et al, 2017), and grade IV, called glioblastoma (GBM), is the most aggressive type of primary brain tumors. Targeting apoptotic pathways has drawn much interest in cancer therapy, as cancer cell death via apoptosis causes minimal inflammation (Jan, 2019). Induction of apoptosis has shown a limited benefit in glioma treatment to date, probably due to our lack of knowledge on the cellular apoptotic pathways in these tumors (Valdés-Rives et al, 2017). Apoptosis is typically controlled by the cell-surface death receptor-mediated extrinsic pathway and
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