ERK inhibition sensitizes cancer cells to oleanolic acid-induced apoptosis through ERK/Nrf2/ROS pathway

Oleanolic acid (OA) is a natural triterpenoid that is widely distributed in edible and medicinal plants. OA exerts anti-tumor activity on a wide range of cancer cells primarily through inducing apoptosis. Dysregulated ERK signaling is closely complicated in the biology of cancer, such as metastasis, proliferation, and survival, and it can be activated by various stimuli. In this study, we found that OA induced the activation of ERK in cancer cells. ERK activation compromised the apoptosis induced by OA. Blocking ERK activation by U0126 or siRNAs was able to potentiate the pro-apoptotic activity of OA on cancer cells. OA was shown to promote ERK-dependent Nrf2 expression in cancer cells, and in turn, Nrf2 expression was able to suppress OA-induced ROS generation. Blockade of Nrf2 expression was able to increase ROS levels and apoptotic death in cancer cells. In conclusion, we provided evidences that ERK activation is a mechanism underlying the resistance of cancer cells to OA-induced apoptosis and targeting ERK is a promising strategy to enhance the anti-tumor efficacy of OA.