Attenuation of cadmium-induced necrotic cell death by necrostatin-1: potential necrostatin-1 acting sites.
Cadmium (Cd) induces necrotic death in Chinese hamster ovary (CHO) K1 cells and we have established the responsible signaling pathway. Reportedly, necrostatin-1 (Nec-1) rescues cells from necrotic death by mediating through the death domain receptor (DR) signaling pathway. We show here that Nec-1 also effectively attenuates necrotic death triggered by Cd. Two other treatments that cause necrotic cell death, one can (z-VAD-fmk/TNF-alpha on U937 cells) and the other cannot (etherynic acid (EA) on DLD-1 cells) be rescued by Nec-1, were also studied in parallel for comparison. Results show that Nec-1 is ineffectual in modulating intracellular calcium contents, calpain activity (a downstream protease), or reactive oxygen species production. It can counteract the reduction in mitochondrial membrane potential (MMP) caused by treating CHO K1 or U937 cells with necrosis-inducing agent. However, this effect was not found in EA-treated DLD-1 cells. Notably, Nec-1 elevates NF-kappaB activity in the presence or absence of necrosis-inducing agents. Our study shows that, in addition to DR-mediated necrosis, Nec-1 is effective in attenuating Cd-induced necrosis. It rescues cells with reduced MMP implying that mitochondrion is its major acting site.
Hsu
Tzu-Sheng
TS
Institute of Molecular and Cellular Biology and Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
Yang
Pei-Ming
PM
Tsai
Jia-Shiuan
JS
Lin
Lih-Yuan
LY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016466:CHO Cells; D002105:Cadmium Poisoning / Q000473:pathology / Q000517:prevention & control*; D020013:Calcium Signaling / Q000187:drug effects; D002154:Calpain / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology; D009336:Necrosis; D011419:Propidium; D017382:Reactive Oxygen Species / Q000378:metabolism; D011955:Receptors, Drug / Q000187:drug effects; D014162:Transfection; D020298:U937 Cells
D002614:Chelating Agents; D007093:Imidazoles; D007211:Indoles; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D011955:Receptors, Drug; C507699:necrostatin-1; D011419:Propidium; D002154:Calpain