title: Proteasome inhibitor MG132 induces selective apoptosis in glioblastoma cells through inhibition of PI3K/Akt and NFkappaB pathways, mitochondrial dysfunction, and activation of p38-JNK1/2 signaling.
abstract: Proteasome inhibitors are emerging as a new class of anticancer agents. In this work, we examined the mechanisms underlying cytotoxicity, selectivity and adjuvant potential of the proteasome inhibitor MG132 in a panel of glioblastoma (GBM) cells (U138MG, C6, U87 and U373) and in normal astrocytes. MG132 markedly inhibited GBM cells growth irrespective of the p53 or PTEN mutational status of the cells whereas astrocytic viability was not affected, suggesting a selective toxicity of MG132 to cancerous glial cells. Mechanistically, MG132 arrested cells in G2/M phase of the cell cycle and increased p21(WAF1) protein immunocontent. Following cell arrest, cells become apoptotic as shown by annexin-V binding, caspase-3 activation, chromatin condensation and formation of sub-G1 apoptotic cells. MG132 promoted mitochondrial depolarization and decreased the mitochondrial antiapoptotic protein bcl-xL; it also induced activation of JNK and p38, and inhibition of NFkappaB and PI3K/Akt survival pathways. Pre-treatment of GBMs with the mitochondrial permeability transition pore inhibitor, bongkrekic acid, or pharmacological inhibitors of JNK1/2 and p38, SP600125 and SB203580, attenuated MG132-induced cell death. Besides its apoptotic effect alone, MG132 also enhanced the antiglioma effect of the chemotherapeutics cisplatin, taxol and doxorubicin in C6 and U138MG cells, indicating an adjuvant/chemosensitizer potential. In summary, MG132 exerted profound and selective toxicity in GBMs, being a potential agent for further testing in animal models of the disease.
authors.affiliation: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brasil. alfeuzanotto@hotmail.com
authors.forename: Alfeu
authors.initials: A
authors.lastname: Zanotto-Filho
authors.forename: Elizandra
authors.initials: E
authors.lastname: Braganhol
authors.forename: Ana Maria Oliveira
authors.initials: AM
authors.lastname: Battastini
authors.forename: José Cláudio Fonseca
authors.initials: JC
authors.lastname: Moreira
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005909:Glioblastoma; D006801:Humans; D007976:Leupeptins / Q000008:administration & dosage*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D017239:Paclitaxel / Q000008:administration & dosage; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061988:Proteasome Inhibitors / Q000008:administration & dosage*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000277:Adjuvants, Pharmaceutic; D000970:Antineoplastic Agents; D007976:Leupeptins; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061988:Proteasome Inhibitors; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; D017239:Paclitaxel; D002945:Cisplatin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde