title: Oncrasin targets the JNK-NF-κB axis to sensitize glioma cells to TNFα-induced apoptosis.
abstract: Resistance of glioblastoma multiforme (GBM) to tumor necrosis factor (TNF) α-induced apoptosis have been attributed to increased nuclear factor-kappaB (NF-κB) activation. As we have previously reported that certain anticancer chemotherapeutics can sensitize glioma cells to TNFα-induced apoptosis by abrogating NF-κB activation, we investigated the potential of oncrasin in sensitizing glioma cells to TNFα-induced apoptosis. Oncrasin reduced glioma cell viability, inhibited TNFα-mediated NF-κB activation and sensitized cells to TNFα-induced apoptosis. Apoptosis was accompanied by elevated Fas and Fas-associated death domain (FADD) levels, increased caspase-8 activation and formation of death-inducing signaling complex (DISC). Oncrasin also (i) affected expression of cell cycle regulators, (ii) triggered DNA damage response, (iii) induced G(2)/M cell cycle arrest, (iv) decreased telomerase activity, (v) abrogated STAT3 activation and (v) mediated extracellular release of high mobility group box 1 (HMGB1) along with its increased association with nucleosomes. Oncrasin-induced apoptosis did not involve mitochondria. Importantly, oncrasin increased c-jun N-terminal kinase (JNK) phosphorylation and pharmacological inhibition of JNK rescued oncrasin-induced apoptosis. JNK inhibition prevented oncrasin-induced decrease in TNFα-induced NF-κB activity and inhibition of NF-κB increased JNK phosphorylation in TNFα-treated cells. Oncrasin induced DISC formation and inhibited anchorage-independent growth of glioma cells in a JNK-dependent manner. By elucidating the existence of JNK-NF-κB cross-talk that regulates resistance to TNFα-induced apoptosis, this study has highlighted the importance of JNK in regulating viability of glioma cells.
authors.affiliation: National Brain Research Centre,  Manesar, Haryana 122051, India.
authors.forename: Piyushi
authors.initials: P
authors.lastname: Gupta
authors.forename: Deobrat
authors.initials: D
authors.lastname: Dixit
authors.forename: Ellora
authors.initials: E
authors.lastname: Sen
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053181:Caspase 8 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019098:Telomerase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay; D019014:fas Receptor / Q000378:metabolism
chemical_list: C505533:FADD protein, human; C491901:FAS protein, human; D053200:Fas-Associated Death Domain Protein; D024243:HMGB1 Protein; D007211:Indoles; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C532252:oncrasin-1; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases; C509186:TERT protein, human; D019098:Telomerase; D053181:Caspase 8