Journal
CARCINOGENESIS
Volume 34, Issue 2, Pages 388-396Publisher
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgs352
Keywords
-
Categories
Funding
- Department of Biotechnology [BT/PR12924/Med/30/235/09]
- Council of Scientific and Industrial Research (CSIR, Government of India)
Ask authors/readers for more resources
Resistance of glioblastoma multiforme (GBM) to tumor necrosis factor (TNF) alpha-induced apoptosis have been attributed to increased nuclear factor-kappaB (NF-kappa B) activation. As we have previously reported that certain anticancer chemotherapeutics can sensitize glioma cells to TNF alpha-induced apoptosis by abrogating NF-kappa B activation, we investigated the potential of oncrasin in sensitizing glioma cells to TNF alpha-induced apoptosis. Oncrasin reduced glioma cell viability, inhibited TNF alpha-mediated NF-kappa B activation and sensitized cells to TNFa-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 TNF alpha-induced NF-kappa B activity and inhibition of NF-kappa B increased JNK phosphorylation in TNF alpha-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-kappa B cross-talk that regulates resistance to TNF alpha-induced apoptosis, this study has highlighted the importance of JNK in regulating viability of glioma cells.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available