S100A8/9 induces cell death via a novel, RAGE-independent pathway that involves selective release of Smac/DIABLO and Omi/HtrA2.

Ghavami S, Kerkhoff C, Chazin WJ, Kadkhoda K, Xiao W, Zuse A, Hashemi M, Eshraghi M, Schulze-Osthoff K, Klonisch T, Los M
Biochim Biophys Acta. 2008 1783 (2): 297-311

PMID: 18060880 · DOI:10.1016/j.bbamcr.2007.10.015

A complex of two S100 EF-hand calcium-binding proteins S100A8/A9 induces apoptosis in various cells, especially tumor cells. Using several cell lines, we have shown that S100A8/A9-induced cell death is not mediated by the receptor for advanced glycation endproducts (RAGE), a receptor previously demonstrated to engage S100 proteins. Investigation of cell lines either deficient in, or over-expressing components of the death signaling machinery provided insight into the S100A8/A9-mediated cell death pathway. Treatment of cells with S100A8/A9 caused a rapid decrease in the mitochondrial membrane potential (DeltaPsi(m)) and activated Bak, but did not cause release of apoptosis-inducing factor (AIF), endonuclease G (Endo G) or cytochrome c. However, both Smac/DIABLO and Omi/HtrA2 were selectively released into the cytoplasm concomitantly with a decrease in Drp1 expression, which inhibits mitochondrial fission machinery. S100A8/A9 treatment also resulted in decreased expression of the anti-apoptotic proteins Bcl2 and Bcl-X(L), whereas expression of the pro-apoptotic proteins Bax, Bad and BNIP3 was not altered. Over-expression of Bcl2 partially reversed the cytotoxicity of S100A8/A9. Together, these data indicate that S100A8/A9-induced cell death involves Bak, selective release of Smac/DIABLO and Omi/HtrA2 from mitochondria, and modulation of the balance between pro- and anti-apoptotic proteins.

MeSH Terms (22)

Animals bcl-X Protein Calgranulin A Calgranulin B Cell Death Cell Line, Tumor Down-Regulation Dynamins Fas-Associated Death Domain Protein High-Temperature Requirement A Serine Peptidase 2 Humans Intracellular Signaling Peptides and Proteins Mice Mitochondria Mitochondrial Proteins Protein Binding Protein Processing, Post-Translational Receptor for Advanced Glycation End Products Receptors, Immunologic Serine Endopeptidases Signal Transduction X-Linked Inhibitor of Apoptosis Protein

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