The metalloprotease-disintegrin ADAM8 contributes to temozolomide chemoresistance and enhanced invasiveness of human glioblastoma cells.

摘要: Background Despite multimodal treatment, glioblastoma (GBM) therapy with temozolomide (TMZ) remains inefficient due to chemoresistance. Matrix metalloproteinase (MMP) and a disintegrin metalloprotease (ADAM), increased in GBM, could contribute chemoresistance TMZ-induced recurrence of glioblastoma. Methods TMZ inducibility metalloproteases was determined GBM cell lines, primary cells, tissues from recurrent GBM. sensitivity invasiveness cells were assessed the presence inhibitors batimastat (BB-94) marimastat (BB-2516). Metalloprotease-dependent effects on mitochondria pAkt/phosphatidylinositol-3 kinase (PI3K) phosphorylated extracellular signal-regulated 1/2 (pERK1/2) pathways analyzed by fluorescence activated sorting, morphometry, immunoblotting. Invasiveness Matrigel invasion assays. Potential substrates identified proteomics tested for using blocking antibodies. Results induces expression MMP-1, -9, -14, ADAM8 tissues. BB-94, but not BB-2516 (ADAM8-sparing) TMZ-resistant -nonresistant different O(6)-methylguanine-DNA methyltransferase states, suggesting that mediates chemoresistance, which confirmed knockdown, overexpression, or pharmacological inhibition ADAM8. Levels pAkt pERK1/2 correlated expression, survival, invasiveness. Soluble hepatocyte growth factor (HGF) R/c-met CD44 as TMZ-treated cells. Blocking HGF prevented Conclusions causes resistance enhancing pAkt/PI3K, pERK1/2, cleavage R/c-met. Specific can optimize chemotherapy order prevent formation patients.