Fig. 7

Proposed model for IFNγ-induced apoptosis of HNSCC cells. The activation of IFNγ receptor of HNSCC cells with IFNγ results in the activation of JAK-STAT pathway that subsequently enhances the DNA binding activity of the transcription factor interferon regulatory factor-1 (IRF-1) that is essential for the induction IDO expression. The increased level of IDO results in the suppression of the anti-oxidant protein heme oxygenase-1 (HO-1) that, in turn, leads to the accumulation of reactive oxygen species (ROS). The increased accumulation of ROS mediates oxidative stress-associated pathways such as apoptosis signal-regulating kinase 1(ASK1)/c-Jun-N-terminal kinase (JNK)-AP-1/p53, IKK-NF-κB, and p38-ATF-2. The formation of a transcriptional complex from the transcription factors NF-κB, AP-1 and p53 results in the transcriptional activation of the promoter of Noxa protein. The localization of Noxa protein to mitochondria results in the loss of mitochondrial membrane potential (Δψm) that is characterized by the release of cytochrome c (Cyt.C) into the cytoplasm where it initiates apoptosis by formation of apoptosome complex leading to the cleavage of caspase-9, caspase-3 and PARP. Whereas the localization of Noxa to endoplasmic reticulum (ER) results in ER-stress that is associated with the activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring-1α (IRE1α) pathways as well as cleavage of caspase-4 that, in turn, mediates the cleavage of caspase-3