Our data suggest that TRAIL may activate the PI3K/Akt/mTOR pathway to counteract TRAIL-induced apoptosis, leading to TRAIL resistance.
Thus, our results indicate that while TRAIL can cause apoptosis, it also activates the Akt survival pathway to counteract TRAIL-induced apoptosis.
In this study, we showed that while TRAIL induces apoptosis in cancer cells, it also activates several survival pathways, which may counteract TRAIL-induced apoptosis, leading to resistance.
We confirmed that macrophages and IL-1β failed to counteract TRAIL-induced activation of caspase-8 and caspase-9 and subsequent cleavage of PARP in cells that express either dnIκB, dnAKT or dnTCF4 (Fig. 5B).
In this study we demonstrated that TRAIL induced apoptosis of colon cancer cells is inhibited by macrophage derived IL-1β, and showed that macrophages and recombinant IL-1β counteract TRAIL-induced apoptosis through activation of Wnt signaling and stabilization of Snail in tumor cells.
On the other hand, the expression of DcR1 and DcR2 was significantly reduced after harmful ischemia, whereas its expression increased after PC+tMCAO at all the considered reperfusion time intervals, suggesting that a possible buffering role of DcR1-DcR2 isetet into motion to counteract TRAIL-induced neuronal death.
In contrast, c-Myc promotes the responsiveness to TRAIL by inhibiting the expression of FLIP, an inhibitor of TRAIL signaling [15], and by counteracting TRAIL-induced upregulation of mcl-1 and cIAP2, two proteins with intrinsic ability to inhibit apoptosis [16].
Exposure of human colon carcinoma cells to TNFα rapidly activated NF-κB (Fig. 4A), and blocking NF-κB activation significantly increased human colon carcinoma cells to TRAIL-induced apoptosis (Fig. 4B), suggesting that NF-κB does counteract with TRAIL-induced apoptosis.
However, in most cancer cells, survival pathways counteract the effects of TRAIL-induced RCD, which makes sensitizers such as CHX indispensible to overcome this problem.
Since in most cancer cells survival pathways counteract the effects of TRAIL-induced RCD, sensitizers such as cycloheximide (CHX) are frequently added in cell culture to overcome this problem.
Thus, the modulation of these proteins is unlikely to be associated with LBH589-mediated potentiation of TRAIL-induced apoptosis in these cell lines; rather, increase in Bcl-2 and Mcl-1 may counteract LBH589's effect in sensitizing pancreatic cancer cells to TRAIL-induced apoptosis.
