Summary Approximately 50% of children with acute myeloid leukaemia (AML) relapse, despite aggressive chemotherapy. The bone marrow stromal environment protects leukaemia cells from chemotherapy (i.e., stroma-induced chemoresistance), eventually leading to recurrence. Our goal is to delineate the mechanisms underlying stroma-mediated chemoresistance in AML. We used two human bone marrow stromal cell lines, HS-5 and HS-27A, which are equally effective in protecting AML cells from chemotherapy-induced apoptosis in AML-stromal co-cultures. We found that CYR61 was highly expressed by stromal cells, and was upregulated in AML cells by both stromal cell lines. CYR61 is a secreted matricellular protein and is associated with cell-intrinsic chemoresistance in other malignancies. Here, we show that blocking stromal CYR61 activity, by neutralization or RNAi, increased mitoxantrone-induced apoptosis in AML cells in AML-stromal co-cultures, providing functional evidence for its role in stroma-mediated chemoresistance. Further, we found that spleen tyrosine kinase (SYK) mediates CYR61 signalling. Exposure to stroma increased SYK expression and activation in AML cells, and this increase required CYR61. SYK inhibition reduced stroma-dependent mitoxantrone resistance in the presence of CYR61, but not in its absence. Therefore, SYK is downstream of CYR61 and contributes to CYR61-mediated mitoxantrone resistance. The CYR61-SYK pathway represents a potential target for reducing stroma-induced chemoresistance.

Abstract. microRNAs are involved in different cancer-related processes. miR-195, one of the miR-16/15/195/424/497 family members, has been shown to act as a tumor suppressor during tumorigenesis. However, the function of miR-195 in osteosarcoma is still unclear. In our study, the miR-195 expression level was upregulated in osteosarcoma cells, by transfection with miR-195, and the fatty acid synthase (FASN) mRNA and protein expression levels were measured by RT-PCR and western blotting. Cell migration and invasion was measured using wound healing migration and Transwell invasion assays. We found that the upregulation of miR-195 greatly decreased cell invasion and the migration of U2OS. We also identified that FASN may be a direct target of miR-195 by the luciferase activity assay. These findings provide evidence that miR-195 plays a key role in inhibiting osteosarcoma cell migration and invasion through targeting FASN, and strongly suggest that exogenous miR-195 may have therapeutic value in treating osteosarcoma.

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Nearly 40% of children with acute myeloid leukemia (AML) suffer relapse due to chemoresistance, often involving upregulation of the oncoprotein STAT3 (signal transducer and activator of transcription 3). In this paper, rhodium(II)-catalyzed, proximity-driven modification identifies the STAT3 coiled-coil domain (CCD) as a novel ligand-binding site, and we describe a new naphthalene sulfonamide inhibitor that targets the CCD, blocks STAT3 function, and halts its disease-promoting effects in vitro, in tumor growth models, and in a leukemia mouse model, validating this new therapeutic target for resistant AML.

Key Points Atovaquone induces AML blast apoptosis and prolongs survival in AML xenografts. Atovaquone induces proapoptotic signaling and inhibits the mTOR pathway through upregulation of ATF4 and also suppresses OXPHOS.

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In the present study, the effect of fatty acid synthase (FASN) inhibition on cell invasion and migration in vitro was investigated. A recombinant plasmid containing a microRNA targeting the FASN gene was used to inhibit FASN expression in U2‑OS cells. Cell migration and invasion were investigated using wound healing and Transwell invasion assays. We found that cell invasion and migration were suppressed by inhibiting FASN. In addition, the effect of inhibition of FASN on phosphorylation of Akt was investigated by detecting the expression levels of pAkt using western blot analysis. Furthermore, protein expression levels of nuclear factor‑κB (NF‑κB; p65) and matrix metalloproteinase (MMP)‑2 and ‑9 were also measured by western blot analysis. Results demonstrated that expression levels of pAkt, NF‑κB (p65) and MMP‑2 and ‑9 proteins were reduced significantly by inhibiting FASN. Therefore, we confirmed that inhibition of FASN by RNA interference suppresses osteosarcoma cell metastasis via downregulation of the phosphoinositide 3‑kinase/Akt/NF‑κB signaling pathway in vitro.

1,2-Dimethoxyethane (DME) has been considered as the most promising electrolyte solvent for Li-metal batteries (LMBs). However, challenges arise from insufficient Li Coulombic efficiency (CE) and poor anodic stability associated with DME-based electrolytes. Here, we proposed a rational molecular design methodology to tailor electrolyte solvation for stable LMBs, where shortening the middle alkyl chain of the solvent could reduce the chelation ability, while increasing the terminal alkyl chain of the solvent could increase the steric hindrance, affording a diethoxymethane (DEM) solvent with ultra-weak solvation ability. When serving as a single solvent for electrolyte, a peculiar solvation structure dominated by contact ion pairs (CIPs) and aggregates (AGGs) was achieved even at a regular salt concentration of 1 m, which gives rise to anion-derived interfacial chemistry. This illustrates an unprecedentedly high Li||Cu CE of 99.1% for a single-salt single-solvent (non-fluorinated) electrolyte at ∼1 m. Moreover, this 1 m DEM-based electrolyte also remarkably suppresses the anodic dissolution of Al current collectors and significantly improves the cycling performance of high-voltage cathodes. This work opens up new frontiers in engineering electrolytes toward stable LMBs with high energy densities.