The Effects Of MEK/ERK And PI3K/Akt Signaling Pathways In Regulating Tumor Cell Sensitivity To TRAIL

TNF-related apoptosis-inducing ligand (TRAIL), a member of TNF family, attracts particular attention for its unique properties to induce cell apoptosis in many kinds of cancer cells while sparing most normal cells. However, there are also some kinds of tumor cells which are TRAIL-resistant and people have closely focused on this phenomenon.Many studies have shown that PI3K/Akt and MEK/ERK signaling pathways play important roles in transmitting stimuli signals, modulating gene expression and inhibiting cell apoptosis. In some types of tumor cells, LY294002, the inhibitor of PI3K, or MEK1/2 inhibitor can obviously increase the ratio of cell apoptosis induced by TRAIL.In our studies, LY294002 degraded cell sensitivity to TRAIL and U0126 had opposite effect; using them together made TRAIL-sensitive U937 cells become resistant to TRAIL. In K562 cells, these two inhibitors working together made cells become much more sensitive to TRAIL than using only one inhibitor. These results showed that, PI3K/Akt and MEK/ERK signaling pathways may have some "cross-talk" and act together in regulating TRAIL sensitivity of tumor cells.Further studies found that Akt and ERKl/2 phosphorylation were both inhibited with the incubation of TRAIL during the time period in U937 cells but K562 cells had different phenomena under the treatment of TRAIL. In K562 cells, stimulation of TRAIL rapidly induced Akt phosphorylation. The activation of Akt appeared 30min after TRAIL treatment and was down-regulated after 1h while the ERKl/2 phosphorylation was decreased at the first hour, began to reverse at the second hour and exceeded the basal level in the end. These two types of cells had a similar phenomenon: the activation of PI3K/Akt signaling pathway would obviously decrease the phosphorylation level of ERKl/2 induced by TRAIL. Over-expression of Akt and stimulating it with TRAIL would inhibit the activation of ERKl/2 and lead to cell apoptosis more quickly in U937 cells. However, the activation of ERKl/2 would reduce TRAIL sensitivity of U937 cells. Moreover, both PI3K/Akt and MEK/ERK pathways are involved in regulating Bad phosphorylation and they have the opposite effects.All these findings indicate that the activation of MEK/ERK signaling pathway plays an important role in regulating TRAIL sensitivity of U937 and K562 cells. The higher level of ERK1/2 phosphorylation will lead to TRAIL resistance, in the contrary, the lower phosphorylation level will increase cell apoptosis ratio. Furthermore, the activation of PI3K/Akt signaling pathway can decline ERK1/2 phosphorylation level. These two pathways work together to regulate TRAIL sensitivity of tumor cells.