Procyanidins from Cinnamomi Cortex promote proteasome-independent degradation of nuclear Nrf2 through phosphorylation of insulin-like growth factor-1 receptor in A549 cells.

Many lines of evidence demonstrate that transcription factor nuclear factor-E2-related factor 2 (Nrf2) plays essential roles in cancer cell proliferation and resistance to chemotherapy, thereby indicating that suppression of abnormal Nrf2 activation is needed for a new therapeutic approach. Our previous studies reported that procyanidins prepared from Cinnamomi Cortex extract (CCE) have an ability to suppress cytoprotective enzymes and cell proliferation in human cancer cells with activated Nrf2. In the present study, we investigated the mechanism of CCE procyanidin-mediated antagonization of Nrf2. CCE procyanidin treatment rapidly reduced nuclear Nrf2 expression and phosphorylated insulin-like growth factor-1 receptor (IGF-1R) in A549 cells. Nrf2 protein expression in A549 cells with reduced IGF-1R expression and function was not affected by treatment with CCE procyanidins, which suggested that CCE procyanidins decreased Nrf2 through IGF-1R. Nrf2 suppression by CCE procyanidins was mitigated in the presence of protease inhibitors, not proteasome inhibitors. In addition, CCE procyanidin treatment led to enhancement of nuclear cysteine protease activity in A549 cells. Our findings suggest a novel mechanism by which CCE procyanidins can promote proteasome-independent degradation of nuclear Nrf2 through IGF-1R phosphorylation and cysteine protease activation.