Mechanism of Tumour-Associated Macrophage-Derived Exosomes in Chemo-Sensitivity of Laryngeal Cancer by Regulating Aerobic Glycolysis via WTAP/GLUT-1.

Abstract

Laryngeal cancer (LC) is a condition characterised by cancerous cell development in laryngeal tissues. This article focuses on the mechanism of tumour-associated macrophage-derived exosomes (TAM-Exos) in LC chemosensitivity by mediating Wilms' tumour 1-associating protein (WTAP)/glucose transporter-1 (GLUT-1). Human peripheral blood mononuclear cells (PBMCs) were cultured in vitro. Macrophage colony-stimulating factor (M-CSF) was used to induce the differentiation of PBMCs into human peripheral blood macrophages (M0), which were further induced into tumour-associated macrophages-educated macrophages (TAMEMs^C-h) by 20% human recombinant protein cocktail and transfected with sh-WTAP. TU686 cells were treated with TAMEMs^C-h derived Exos, cisplatin (DDP), 2-deoxyglucose, and small-interfering-GLUT-1, with TAMEMs^C-h morphology and phenotype assessed. Finally, nude mice were treated with DDP and Exos for in vivo verification. TAMEMs^C-h-derived Exos promoted aerobic glycolysis and reduced LC cell sensitivity to DDP. TAMEMs^C-h-derived Exos increased glucose uptake, lactic acid, lactate dehydrogenase, and adenosine triphosphate levels, facilitated aerobic glycolysis, viability, and invasion, and decreased apoptotic rate by mediating WTAP, thus reducing DDP sensitivity in TU686 cells. But the effect of TAM-Exos was reversed in response to aerobic glycolysis suppression or GLUT-1 knockdown. TAM-Exos carrying WTAP increased GLUT-1 N6-methyladenosine (m6A) modification and GLUT-1 messenger RNA (mRNA) stability, hence boosting GLUT-1 expression. TAM-Exos boosted aerobic glycolysis by mediating WTAP/GLUT-1, thus decreasing DDP sensitivity and enhancing tumour growth. TAM-Exos promoted the m6A modification of GLUT-1 through WTAP, and improved GLUT-1 mRNA stability and expression, thereby promoting aerobic glycolysis and reducing the chemo-sensitivity of LC.