Figure 9
A working model for the synergistic effect of APG and TRAIL on NSCLC cells.
APG treatment induces c-Jun N-terminal kinase (JNK) and subsequent c-Jun and p53 activation in NSCLC cells. The activation of p53 thus contributes to the upregulation of DR4 and DR5 levels. When NSCLC cells are treated with the combination of APG and TRAIL, TRAIL stimulates overexpressed DR4 and DR5, inducing the activation of caspase-8, which degrades Bid to t-Bid. Additionally, p53 accumulation accounts for the decrease in Bcl-2 level and also upregulates Bax level, contributing to Bax oligomerization. Furthermore, APG and TRAIL combined treatment inhibits AKT phosphorylation via the PI3K inhibition, which contributes to IκBα phosphorylation inhibition and degradation, suppresses the nuclear translocation of p65, and, in turn, decreases the expression of NF-κB target genes, such as c-FLIP, Bcl-2 and Bcl-xl. Thus, the increase in the Bax:Bcl-2 ratio induces the depolarization of the mitochondrial membrane with the release of cytochrome c and the consequent activation of caspase-9 and caspase-3, resulting in apoptosis of NSCLC cells. Moreover, the combination of APG and TRAIL also suppresses the activation of ERK pathway. All of the above finally sensitize NSCLC cells to TRAIL-induced apoptosis.
