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Necrotic debris and STING exert therapeutically relevant effects on tumor cholesterol homeostasis

ABSTRACT: Necrosis is a common feature of most solid malignant tumors and a major consequence of chemotherapy. The debris released by necrotic cells includes many damage/danger-associated molecular patterns (DAMPs) that stimulate cell surface and intracellular pattern recognition receptors (PRRs) activation. Treatment of Ewing’s sarcoma with conventional chemotherapy has reached a plateau in efficacy. The inability to target the fusion protein responsible for its pathogenesis warrants the quest for alternative therapeutic strategies. We have shown that DAMPs released by necrotic cells can stimulate the growth of EwS cells cultured in 3D and that of the related tumors in vivo. In stark contrast, we observed that STING, a signaling platform that responds to nucleic acids released from damaged nuclei, opposed the effect of DAMPs on EwS cell growth in vitro and tumor growth in vivo, maintaining cholesterol homeostasis. Our observations suggest that STING activation in conjunction with cholesterol-reducing agents may offer an unsuspected approach to control EwS growth.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184421 | GEO | 2021/12/27

REPOSITORIES: GEO

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Project description:Endogenous damage associated molecular pattern molecules (DAMPs) released from necrotic, damaged or stressed cells are associated with an inflammatory response. Whether the microRNA expression signature of this response is different from that of a PAMP-stimulated inflammatory response is unknown. We report here that miR-34c and miR-214 are significantly expressed in fresh human PBMCs exposed to DAMPcontaining freeze-thaw lysates, or to conditioned media from serum-starved and glucose-deprived cells (p<6x10-4 and p<3.7x10-3), respectively. Interestingly, only miR-34c expression was differentially expressed in PBMCs exposed to freeze-thaw lysates or conditioned media from HMGB1+/+ mouse embryonic fibroblast (MEF) cells, when compared to cultures exposed to lysates or conditioned media from HMGB1-/- MEFs. miR-155 expression in these cultures was negligible, but was significantly higher in PBMCs stimulated with LPS or most other TLR ligands, making it the prototypic PAMPmiR. Exposure to a damaged human colorectal carcinoma cell line lysate (HCT116) similarly resulted in increased miR-34c and miR-214 levels. When PBMCs were pre-transfected with anti-miR-34c and then exposed to lysate, expression levels of IKKgamma mRNA, a putative target of miR-34c, increased, while protein levels of IKKgamma in cultures transfected with a pre-miR-34c were abrogated. Levels of miR-34c expression (as well as pro-inflammatory cytokines, IL-1beta and TNFalpha) decreased when PBMC cultures were briefly pre-incubated with the K+ channel (inflammasome) inhibitor, glybenclamide, suggesting that miR-34c is involved in the inflammasome pathway in response to DAMPs. Our findings suggest that a specific microRNA expression signature is associated with the inflammatory response to damaged/injured cells and carries implications for many acute and chronic inflammatory disorders. Human PBMC (peripheral blood mononuclear cells) were exposed to 4 conditions for 48 hours. In the first condition, PBMCs were exposed to conditioned media from serum-starved and glucose-deprived and heat shocked HMGB1-/- MEF cells (mouse embryonic fibroblast cells). In the second condition, PBMCs were exposed to conditioned media from serum-starved and glucose-deprived and heat shocked HMGB1+/+ MEF cells (mouse embryonic fibroblast cells). In the third condition, PBMCs were exposed to LPS (Lipopolysaccharide). In the fourth condition, the PBMCs where left untreated. Four biological repeats were done for each condition for a total of 16 samples.

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Necrotic debris and STING exert therapeutically relevant effects on tumor cholesterol homeostasis

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