S100A8/9 induces cell death via a novel, RAGE-independent pathway that involves selective release of Smac/DIABLO and Omi/HtrA2.
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.
Ghavami
Saeid
S
Manitoba Institute of Cell Biology, Canada.
Kerkhoff
Claus
C
Chazin
Walter J
WJ
Kadkhoda
Kamran
K
Xiao
Wenyan
W
Zuse
Anne
A
Hashemi
Mohammad
M
Eshraghi
Mehdi
M
Schulze-Osthoff
Klaus
K
Klonisch
Thomas
T
Los
Marek
M
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D040501:Calgranulin A / Q000378:metabolism*; D040502:Calgranulin B / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D034281:Dynamins / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D040501:Calgranulin A; D040502:Calgranulin B; C412403:DIABLO protein, human; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse; D034281:Dynamins