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S100A8/9 induces cell death via a novel, RAGE-independent pathway that involves selective release of Smac/DIABLO and Omi/HtrA2
Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, Cancer Care Manitoba, Winnipeg, Manitoba, Canada.
Institute of Experimental Dermatology, Münster, Germany.
Department of Biochemistry Vanderbilt University, Nashville, USA; Department of Chemistry, Vanderbilt University, Nashville, USA; Center for Structural Biology, Vanderbilt University, Nashville, TN 37232-8725, USA.
Manitoba Institute of Cell Biology, Canada; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada.
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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
Abstract [en]

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.
Keyword [en]
Bcl2 protein family; S100/calgranulin; Cancer regression; Drp1; Receptor for advanced glycated endproducts (RAGE); Mitochondrial fission; XIAP
National Category
Cancer and Oncology Cell Biology Biochemistry and Molecular Biology
URN: urn:nbn:se:liu:diva-86930DOI: 10.1016/j.bbamcr.2007.10.015ISI: 000253270200014PubMedID: 18060880OAI: 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 apoptosis

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