Journal
ONCOTARGET
Volume 6, Issue 28, Pages 25252-25265Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.4487
Keywords
CGK733; calcium sequestration; PERK/CHOP; ER stress; non-apoptotic death
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Funding
- ministry of Education, Science, Sports and Culture of Japan [24501352]
- Grants-in-Aid for Scientific Research [24501352] Funding Source: KAKEN
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Calcium ions (Ca2+) are indispensable for the physiology of organisms and the molecular regulation of cells. We observed that CGK733, a synthetic chemical substance, induced non-apoptotic cell death and stimulated reversible calcium sequestration by vesicles in pancreatic cancer cells. The endoplasmic reticulum (ER) stress eukaryotic translation initiation factor 2-alpha kinase 3/C/EBP homologous protein (PERK/CHOP) signaling pathway was shown to be activated by treatment with CGK733. Ionomycin, an ER stress drug and calcium ionophore, can activate PERK/CHOP signaling and accelerate CGK733-induced calcium sequestration. Knockdown of CHOP diminished CGK733-induced vesicular calcium sequestration, but had no effects on the cell death. Proteomic analysis demonstrated that the ER-located calcium-binding proteins, calumenin and protein S100-A11, were altered in CGK733-treated cells compared to non-treated controls. Our study reveals that CGK733-induced intracellular calcium sequestration is correlated with the PERK/CHOP signaling pathway and may also be involved in the dysregulations of calcium-binding proteins.
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