PKCα-GSK3β-NF-κB signaling pathway and the possible involvement of TRIM21 in TRAIL-induced apoptosis.

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a highly promising therapeutic agent for cancer treatment, owing to its ability to selectively target tumor cells for cell death while having little effect on most normal cells. However, recent research has found that many cancers, including non-small cell lung cancer (NSCLC), display resistance to TRAIL. Therefore, it is important to elucidate the molecular mechanisms governing the resistance of tumor cells to TRAIL treatment. In this study, we show that GSK3β antagonized TRAIL-induced apoptosis in H1299 NSCLC cells, and determined that the PKCα isozyme is an upstream regulator of GSK3β that phosphorylates and inactivates GSK3β, thereby sensitizing cancer cells to TRAIL-induced apoptosis. Furthermore, we demonstrated that the anti-apoptotic effect of GSK3β is mediated by the NF-κB pathway, whereas the tripartite motif 21 (TRIM21) was able to inhibit the activation of NF-κB by GSK3β, and leads to the promotion of cell apoptosis. Taken together, our study further delineated the underpinning mechanism of resistance to TRAIL-induced apoptosis in H1299 cells, and provided new clues for sensitizing NSCLC cells to TRAIL therapy.