Tetralol derivative NNC-55-0396 induces glioblastoma cell death by activating IRE1a, JNK1 and calcium signaling

Mibefradil and NNC-55-0396, tetralol derivatives with a proven -ability to block T-type calcium channels in excitable cells, reduce cancer cell viability in vitro, causing cell death. Furthermore, they reduce tumor growth in preclinical models of Glioblastoma multiforme (GBM), a brain tumor of poor prognosis. Here we found that GBM cells treated with cytotoxic concentrations of NNC-55-0396 paradoxically increased cytosolic calcium levels through the activation of inositol triphosphate receptors (IP3R) and ER stress. We used pharmacological inhibitors and gene silencing to dissect the cell death pathway stimulated by NNC-55-0396 in GBM cell lines and biopsy-derived cultures. Calcium chelation or IP3R inhibition prevented NNC-55-0396-mediated cytotoxicity, indicating that ER calcium efflux is the cause of cell death. Upstream of calcium mobilization, NNC-55-0396 activated the IRE1 alpha arm of the Unfolded Protein Response (UPR) resulting in the nuclear translocation of proapoptotic CHOP. Consistent with these findings, silencing IRE1 alpha or JNK1 rescued the cell death elicited by NNC-55-0396. Therefore, we demonstrate that activation of IRE1 alpha and calcium signaling accounts for the cytotoxicity of NNC-55-0396 in GBM cells. The delineation of the signaling pathway that mediates the abrupt cell death triggered by this compound can help the development of new therapies for GBM.

Automated summary

It was found that NNC-55-0396 can induce cell death in GBM cells through the activation of IRE1 alpha and calcium signaling pathway. Understanding the signaling pathway involved in the sudden cell death triggered by this compound can contribute to the development of new therapies for GBM.