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

Abstract

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.

S100A8 and S100A9 Promotes Invasion and Migration through p38 Mitogen-Activated Protein Kinase-Dependent NF-κB Activation in Gastric Cancer Cells

“…These results suggest that extracellular S100A8/A9 promote migration and invasion through interaction with gastric cancer cells. Although S100A8/A9 protein has been shown to exert apoptotic effect against various tumor cells including colon carcinoma cells (Ghavami et al, 2004) and breast cancer cells and neuroblastoma cells (Ghavami et al, 2008a), the effect of S100A8/ A9 on cell viability has been reported to be dependent on concentration exposed. S100A8/A9 resulted in significantly reduced cell viability at concentration above 50 μg/ml, while it at concentration lower than 25 μg/ml promotes proliferation and migration of various cancer cells (Ghavami et al, 2008b;Hermani et al, 2006;Moon et al, 2008).…”

Quantitative Proteomics and Transcriptomics Addressing the Estrogen Receptor Subtype-mediated Effects in T47D Breast Cancer Cells Exposed to the Phytoestrogen Genistein

“…The majority of these myosins are actively involved in cell assembly and organization or cytoskeleton reorganization. Among the several significantly down-regulated proteins, we found at least three proteins, S100A8, S100A9, and PIP, of specific interest because their expression is associated with a decrease of cell proliferation and induction of apoptosis (29,30). The two S100 EF-hand calcium-binding proteins S100A8/A9 induce apoptosis in various cells, especially tumor cells like MCF-7 (29).…”

Cancer stem cell markers in common cancers – therapeutic implications

“…At present, conventional anticancer therapies include chemotherapy, radiation and immunotherapy [97][98][99] and kill rapidly growing differentiated tumor cells, thus reducing tumor mass but potentially leaving behind cancer-initiating cells (Box 2). Therapies that exclusively address the pool of differentiated cancer cells but fail to eradicate the CSC compartment might ultimately result in relapse and the proliferation of therapy-resistant and more aggressive tumor cells, causing the death of the patient.…”