No abstract

Reelin is an extracellular matrix (ECM) protein that is essential for neuron

Reelin is an extracellular matrix protein that is crucial for neuron migration, adhesion, and positioning. We examined the expression of Reelin in a large cohort of multiple myeloma patients recorded in Gene Expression Omnibus (GEO) database and used over-expression and siRNA knockdown of Reelin to investigate the role of Reelin in myeloma cell growth. We find that Reelin expression is negatively associated with myeloma prognosis. Reelin promotes myeloma cell proliferation in vitro as well as in vivo. The Warburg effect, evidenced by increased glucose uptake and lactate production, is also enhanced in Reelin-expressing cells. The activation of FAK/Syk/Akt/mTOR and STAT3 pathways contributes to Reelin-induced cancer cell growth and metabolic reprogramming. Our findings further reveal that activated Akt and STAT3 pathways induce the upregulation of HIF1α and its downstream targets (LDHA and PDK1), leading to increased glycolysis in myeloma cells. Together, our results demonstrate the critical contributions of Reelin to myeloma growth and metabolism. It presents an opportunity for myeloma therapeutic intervention by inhibiting Reelin and its signaling pathways.

High-risk neuroblastoma remains therapeutically challenging to treat, and the mechanisms promoting disease aggression are poorly understood. Here, we show that elevated expression of dihydrolipoamide S-succinyltransferase (DLST) predicts poor treatment outcome and aggressive disease in patients with neuroblastoma. DLST is an E2 component of the α-ketoglutarate (αKG) dehydrogenase complex, which governs the entry of glutamine into the tricarboxylic acid cycle (TCA) for oxidative decarboxylation. During this irreversible step, αKG is converted into succinyl-CoA, producing NADH for oxidative phosphorylation (OXPHOS). Utilizing a zebrafish model of MYCN-driven neuroblastoma, we demonstrate that even modest increases in DLST expression promote tumor aggression, while monoallelic dlst loss impedes disease initiation and progression. DLST depletion in human MYCN-amplified neuroblastoma cells minimally affected glutamine anaplerosis and did not alter TCA cycle metabolites other than αKG. However, DLST loss significantly suppressed NADH production and impaired OXPHOS, leading to growth arrest and apoptosis of neuroblastoma cells. In addition, multiple inhibitors targeting the electron transport chain, including the potent IACS-010759 that is currently in clinical testing for other cancers, efficiently reduced neuroblastoma proliferation in vitro. IACS-010759 also suppressed tumor growth in zebrafish and mouse xenograft models of high-risk neuroblastoma. Together, these results demonstrate that DLST promotes neuroblastoma aggression and unveils OXPHOS as an essential contributor to high-risk neuroblastoma. Significance: These findings demonstrate a novel role for DLST in neuroblastoma aggression and identify the OXPHOS inhibitor IACS-010759 as a potential therapeutic strategy for this deadly disease.

No abstract

Bimodal fluorescence-magnetic resonance imaging (MRI) technique has shown great utilities in bioassays because it combines the advantages of both optical imaging and MRI to provide more sufficient information over any modality alone. In this work, on the basis of a MnO nanosheet-Ru(II) complex nanoarchitecture, a bimodal phosphorescence-MRI nanoprobe for glutathione (GSH) has been constructed. The nanoprobe, Ru(BPY)@MnO, was constructed by integrating MnO nanosheets with a phosphorescent Ru(II) complex [Ru(BPY)](PF) (BPY = 2,2'-bipyridine), which resulted in complete phosphorescence quenching of the Ru(II) complex, accompanied by very low longitudinal and transverse relaxivity. Upon exposure to GSH, the reduction of MnO nanosheets by GSH triggers a recovery of phosphorescence and simultaneously produces a number of Mn ions, a perfect MRI contrast agent. The as-prepared nanoprobe showed good water dispersion and biocompatibility and a rapid, selective, and sensitive response toward GSH in the phosphorescence and MR detection modes. The practicability of the nanoprobe was proved by time-gated luminescence assay of GSH in human serum, phosphorescent imaging of endogenous GSH in living cells, zebrafish, and tumor-bearing mice, as well as the MRI of GSH in tumor-bearing mice. The research outcomes suggested the potential of Ru(BPY)@MnO for the bimodal phosphorescence-MRI sensing of GSH in vitro and in vivo.

New ultrabright fluorescent silica nanoparticles for targeting cancers in vivo are presented.

A novel nanoprobe based on Eu(iii) complex–MnO2 nanosheet nanocomposites has been prepared for dual-modal TGL/MR imaging of GSH in vitro and in vivo.