S100A8/9 induces cell death via a novel, RAGE-independent pathway that involves selective release of Smac/DIABLO and Omi/HtrA2
2008 (English)In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, Vol. 1783, no 2, 297-311 p.Article in journal (Refereed) Published
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 (ΔΨm) 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-XL, 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.
Place, publisher, year, edition, pages
Elsevier, 2008. Vol. 1783, no 2, 297-311 p.
Bcl2 protein family; S100/calgranulin; Cancer regression; Drp1; Receptor for advanced glycated endproducts (RAGE); Mitochondrial fission; XIAP
Cancer and Oncology Cell Biology Biochemistry and Molecular Biology
IdentifiersURN: urn:nbn:se:liu:diva-86930DOI: 10.1016/j.bbamcr.2007.10.015ISI: 000253270200014PubMedID: 18060880OAI: oai:DiVA.org:liu-86930DiVA: diva2:583327
ΔΨm, mitochondrial membrane potential; AIF, apoptosis-inducing factor; BH3, Bcl2 homology 3; BNIP3, Bcl2/adenovirus E1B 19 kD-interacting protein 3; DD, death domain; DED, death effector domain; DISC, death inducing signaling complex; Drp, dynamin-related protein; DTPA, diethylene triamine pentaacetate; Endo G, endonuclease G; FADD, Fas-Associated Death Domain; FADD-DN, dominant-negative FADD mutant; HtrA2, high-temperature requirement A2; IAPs, inhibitors of apoptosis; IM, inner membrane; JC-1, 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide; MTT, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide; RAGE, receptor for advanced glycation endproducts; ROS, reactive oxygen species; Smac/DIABLO, second mitochondrial activator of caspases/direct inhibitor of apoptosis binding protein of low PI; XIAP, X-linked inhibitor of apoptosis2013-01-072013-01-072013-09-03