p38 MAPK signaling mediates mitochondrial apoptosis in cancer cells induced by oleanolic acid

Oleanolic acid (OA) is a nutritional component widely distributed in various vegetables. Although it has been well recognized for decades that OA exerts certain anti-tumor activity by inducing mitochondria-dependent Apoptosis, it is still unclear that what molecular signaling is responsible for this effect. In this study, we employed Cancer cell lines, A549, BXPC-3, PANC-1 and U2OS to elucidate the molecular mechanisms underlying OA anti- tumor activity. We found that activation of MAPK pathways, including p-38 MAPK, JNK and ERK, was triggered by OA in both a dose and time-dependent fashion in all the tested Cancer cells. Activation was accompanied by cleavage of caspases and PARP as well as cytochrome C release. SB203580 (p38 MAPK Inhibitor), but not SP600125 (JNK Inhibitor) and U0126 (ERK Inhibitor), rescued the pro-apoptotic effect of OA on A549 and BXPC- 3 cells. OA induced p38 MAPK activation promoted mitochondrial translocation of Bax and Bim, and inhibited Bcl-2 function by enhancing their phosphorylation. OA can induce Reactive Oxygen Species (ROS)-dependent ASK1 activation, and this event was indispensable for p38 MAPK-dependent Apoptosis in Cancer cells. In vivo, p38 MAPK knockdown A549 tumors proved resistant to the growth-inhibitory effect of OA. Collectively, we elucidated that activation of ROS/ASK1/p38 MAPK pathways is responsible for the Apoptosis stimulated by OA in Cancer cells. Our finding can contribute to a better understanding of molecular mechanisms underlying the antitumor activity of nutritional components.