Independent activation of Akt and NF‐kappaB pathways and their role in resistance to TNF‐α mediated cytotoxicity in gliomas

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Abstract
Tumor associated macrophages (TAMs) constitute a substantial mass in gliomas. The activated macrophages secrete various cytokines that affect diverse functions of tumors. The aim of this study was to elucidate the role of Akt and NF-κB pathways in resistance to TNF-α mediated cell death in human gliomas using monolayers and multicellular spheroids (MCS) as in vitro models. Akt and NF-κB are constitutively expressed and intimately involved in progression of gliomas. The activation of these pathways also renders the tumors resistant to conventional treatments including chemotherapy. While PI3K/Akt is shown to regulate the NF-κB activation in diverse systems, other studies place NF-κB upstream of Akt activation. Using a stable IκBα mutant LN-18 cell line and pharmacological inhibitors to PI3K/Akt (LY294002) and Akt (Akt2), we provide evidence that Akt and NF-κB are activated independently on stimulation with TNF-α and both the pathways contribute towards resistance to TNF-α mediated cell death. TNF-α-induced NF-κB activation independent of PI3K/Akt pathway was also confirmed in human glioma cell lines-LN-229 and U373MG. We also show that NF-κB and Akt are activated during spheroidogenesis and their expression is further enhanced on stimulation with TNF-α implicating their involvement in resistance to cell death. The findings thus underscore the relevance of spheroids as appropriate in vitro models for studying the signaling pathways in drug induced resistance.