RESUMO
Gastrointestinal stromal tumors (GISTs) are primarily characterized by activating mutations of tyrosine kinase or platelet-derived growth factor receptor alpha. Although the revolutionary therapeutic outcomes of imatinib are well known, the long-term benefits of imatinib are still unclear. The effects of BRD9, a recently identified subunit of noncanonical BAF complex (ncBAF) chromatin remodeling complexes, in GISTs are not clear. In the current study, we evaluated the functional role of BRD9 in GIST progression. Our findings demonstrated that the expression of BRD9 was upregulated in GIST tissues. The downregulation or inhibition of BRD9 could significantly reduce cellular proliferation, and facilitates apoptosis in GISTs. BRD9 inhibition could promote PUMA-dependent apoptosis in GISTs and enhance imatinib activity in vitro and in vivo. BRD9 inhibition synergizes with imatinib in GISTs by inducing PUMA upregulation. Mechanism study revealed that BRD9 inhibition promotes PUMA induction via the TUFT1/AKT/GSK-3ß/p65 axis. Furthermore, imatinib also upregulates PUMA by targeting AKT/GSK-3ß/p65 axis. In conclusion, our results indicated that BRD9 plays a key role in the progression of GISTs. Inhibition of BRD9 is a novel therapeutic strategy in GISTs treated alone or in combination with imatinib.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Proteínas Proto-Oncogênicas/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Dano ao DNA/genética , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Mesilato de Imatinib/farmacologia , Masculino , Camundongos Nus , Pessoa de Meia-Idade , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The purpose of this study was to use polymeric liposomes (PLs) with a targeting ligand (folate) to coat superparamagnetic iron oxide nanoparticles (SPIONs) and transfer the magnetic nanoparticles from organic phases to aqueous solutions, and further evaluate their efficacy as a magnetic resonance imaging (MRI) contrast agent. The formed nanoparticles exhibited a narrow range of size dispersity (core size of the particles is about 8-10 nm) and relatively high T2 relaxivities (r2 = 164.14 s(-1) mM(-1) for folate-PLs-coated SPIONs). The in vitro tumor cell targeting efficacy of the folate functionalized and PLs-coated SPIONs was evaluated upon observing cellular uptake of magnetite liposomes by HeLa cells, which overexpresses surface receptors for folic acid. In the Prussian blue staining experiments, cells incubated with folate-PLs-coated SPIONs showed much higher intracellular iron density than did the cells incubated with the folate-free PLs-coated SPIONs. Meanwhile, the MTT assay explains the negligible cell cytotoxicity of SPIONs and folate-PLs-coated SPIONs. In HeLa cells, the in vitro MRI study also indicates the better T2-weighted images in folate-PLs-coated SPIONs than in folate-free PLs-coated SPIONs.