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α7 Nicotinic Acetylcholine Receptor-Associated Signaling in U87MG Glioblastoma Cells (LFQ, Orbitrap Elite)

ABSTRACT: This project investigates the role of α7 nicotinic acetylcholine receptor (α7 nAChR) signaling in glioblastoma using the U87MG human glioblastoma cell line. Cells were treated with selective α7 nAChR ligands (10 μM of agonist PNU282987, 1 μM of positive allosteric modulator PNU120596, 1 μM of antagonist α-cobratoxin) and their combination. Whole-cell lysates were processed for total proteome analysis, proteins were digested in-solution with trypsin and peptides analyzed by nano-ESI-LC-MS/MS on a Thermo Orbitrap Elite using DDA. Data were searched with PEAKS Studio 11 against the UniProtKB Human database and quantified by label-free quantification (LFQ). Proteomic changes in cytoskeletal, metabolic and ER-associated proteins were detected.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Malignant Cell

DISEASE(S): Brain Glioblastoma Multiforme

SUBMITTER: Elena Gondarenko

LAB HEAD: Igor Kasheverov

PROVIDER: PXD070911 | Pride | 2026-06-08

REPOSITORIES: Pride

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Project description:The cellular origin and molecular progression towards aggressive cancers such as acute myeloid leukemia (AML) remain elusive. Clinically, Myelodysplastic syndromes (MDS) and related myeloproliferative neoplasias (MPN) disorders1-5 are believed to present as a precursor stage to lethal AML development. Despite the identification of cytogenetic abnormalities and increased activation of signaling in human MDS/MPN, specific pathways that either sustain or initiate disease progression and evolve into self-sustaining leukemic-initiating cells (L-ICs)13 have not been elucidated. Here we demonstrate that tissue specific loss of glycogen synthase kinase-3Î² (GSK3 betaÎ²) initiates the emergence of stable Pre-leukemic-ICs (PLIC) in vivo. In contrast to deletion or transgenic perturbation of pathways associated with AML eg. Î²-catenin/Wnt, serial transplantation of PL-IC produced abnormal hematological disease that phenotypically and molecularly resembles human MDS/MPN. PL-ICs were exclusively generated from GSK3 betaÎ² deficient hematopoietic stem cells (HSCs), indicating that disease initiation events collaborate with existing HSC self-renewal machinery. In the absence of GSK3 betaÎ², subsequent deletion of GSK3 betaÎ± caused rapid induction of L-ICs that give rise to lethal AML. As these processes were solely driven by dose-dependent deficiencies in GSK3 beta levels, our results suggest that perturbation of this pathway can sufficiently drive and recapitulate a step-wise progression of disease from HSCs to MDS/MPN and subsequent AML. Our study provides a molecular and cellular foundation to understand AML evolution from pre-leukemic precursors. We suggest that defining the molecular states of pre-neoplastic disease will allow patient stratification at early stages of MDS/MPN onset and aid in the development of therapeutic targeting of causal pathways responsible for the earliest stages of leukemic initiation events. 5 week post-transplanted recipient mice (CD45.1) with either Lin- bone marrow GSK3 alpha +/+ beta +/flx, alpha+/+ beta flx/flx, alpha -/- beta +/+ or alpha-/- beta fx/flx Rosa26-CreERTM cells (CD45.2) were induced 3 times with intraperitoneal injections of Tamoxifen (75mg/kg) at intervals of two to three days. Mice were sacrificed and analyzed 4 weeks after injection. Bone marrow lineage negative (Lin-), Sca1+, cKit+ cells were sorted from engrafted Lin- bone marrow GSK3 alpha +/+ beta +/flx, alpha+/+ beta flx/flx, alpha -/- beta +/+ or alpha-/- beta fx/flx cells for RNA extraction. Total RNA from purified populations was extracted and amplified as described previously (Shojaei et al., 2005). Amplified-labeled RNA was hybridized to Affymetrix Mouse Genome 430 2.0 Array.

			Action	DRS
	U87_ALL_1-1.mzML	Mzml
	U87_ALL_1-2.mzML	Mzml
	U87_ALL_2-1.mzML	Mzml
	U87_ALL_2-2.mzML	Mzml
	U87_ALL_3-1.mzML	Mzml

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α7 Nicotinic Acetylcholine Receptor-Associated Signaling in U87MG Glioblastoma Cells (LFQ, Orbitrap Elite)

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