Abstract
Tumor cells strategically down-regulate Fas receptor expression to evade immune attack and up-regulate expression of Fas ligand to promote apoptosis of infiltrating T lymphocytes. Many pathways leading to apoptotic cell death require calcium release from inositol 1,4,5-trisphosphate receptors (IP3Rs). Here, we show that Fas-dependent killing of Jurkat T lymphoma cells by SW620 colon cancer cells requires calcium release from IP3R. General suppression of IP3R signaling significantly reduced SW620-mediated Jurkat cell apoptosis. Significantly, a specific inhibitor of apoptotic calcium release from IP3R strongly blocked lymphocyte apoptosis. Thus, selective pharmacological targeting of apoptotic calcium release from IP3R may enhance tumor cell immunogenicity.
Highlights
Tumor cells strategically down-regulate Fas receptor expression to evade immune attack and up-regulate expression of Fas ligand to promote apoptosis of infiltrating T lymphocytes
Apoptosis-specific signaling via IP3R is mediated by cytochrome c, which binds to the channel after being released from mitochondria, resulting in augmented channel function [13]
We show that inhibiting IP3R function in Jurkat T-lymphoma cells is cytoprotective against apoptosis induced by co-culture with Fas ligand-expressing SW620 colon cancer cells
Summary
Requirement of Inositol 1,4,5-Trisphosphate Receptors for Tumor-mediated Lymphocyte Apoptosis*. Many pathways leading to apoptotic cell death require calcium release from inositol 1,4,5-trisphosphate receptors (IP3Rs). Apoptosis-specific signaling via IP3R is mediated by cytochrome c, which binds to the channel after being released from mitochondria, resulting in augmented channel function [13]. This leads to cytosolic and mitochondrial calcium overload and cell death. We hypothesized that inhibiting IP3R-dependent apoptotic signaling in lymphocytes would protect them from apoptotic cell death induced by tumor cells expressing high levels of Fas ligand. We show that inhibiting IP3R function in Jurkat T-lymphoma cells is cytoprotective against apoptosis induced by co-culture with Fas ligand-expressing SW620 colon cancer cells. Targeting proapopotic signaling through the IP3R in lymphocytes appears to be a promising therapeutic approach for enhancing tumor cell immunogenicity
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