Accumulation of Cytosolic Calcium Induces Necroptotic Cell Death in Human Neuroblastoma

Abstract

Necrosis has been studied extensively since the early days of medicine, with some patterns of necrosis found to be programmed like apoptotic cell death. However, mechanisms of programmed necrosis (necroptosis) are yet to be fully elucidated. In this study, we investigated how the hemagglutinating virus of Japan-envelope (HVJ-E) induces necrosis in mouse xenografts of human neuroblastoma cells. HVJ-E-induced necrosis in this system was found to depend on phosphorylation of the death receptor kinase receptor interacting protein kinase 1 (RIP1) and on the production of reactive oxygen species. This process was interpreted as necroptosis, based on its suppression by the small molecule necrostatin-1, and it did not involve the TNF-a receptor pathway. We also demonstrated that increased concentrations of cytoplasmic calcium triggered necroptosis by activating calcium-calmodulin kinase (CaMK) II. Finally, we determined that RIP1 phosphorylation was mediated by CaMK II activation. Together, our results define an upstream pathway for the activation of necroptosis in neuroblastoma cells, with potential therapeutic implications. Cancer Res; 74(4); 1056-66. Ó2013 AACR.

A Computational Model of Motor Neuron Degeneration

“…Sustained increased cytosolic Ca ++ , upon reaching the soma, can modulate transcriptional programs, which, incidentally, may not all be pro-degenerative (Cho et al, 2013). Nonetheless, increased intracellular Ca ++ has been linked to the activation of necroptosis (Nomura et al, 2014), a form of programmed necrosis that has been shown to drive the death of motor neurons in animal models of both mutant SOD1 and sporadic ALS (Re et al, 2014). …”

Cytoplasmic calcium increase via fusion with inactivated Sendai virus induces apoptosis in human multiple myeloma cells by downregulation of c-Myc oncogene

“…Previous studies have shown that HVJ-E-mediated cell death is induced by the recognition of HVJ-E RNA genome fragments with RNA receptor retinoic-acid inducible gene-I (RIG-I) or an elevation of the cytosolic Ca 2+ concentration [26, 34]. We found that HVJ-E failed to induce RIG-I expression in MM cells (NCI-H929, U266 and MM1S; Supplementary Figure 4A).…”

Inactivated Sendai virus induces apoptosis and autophagy via the PI3K/Akt/mTOR/p70S6K pathway in human non-small cell lung cancer cells

“…A recent report revealed that HVJ-E-induced cell death in human neuroblastoma cells depends on necrosis rather than apoptosis [19]. However, our previous studies showed that HVJ-E-induced apoptosis depends on caspase-8 activation in PC3 human prostate cancer cells and caspase-9 activation in murine B16F10 melanoma cells [6,7].…”