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.