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http://dx.doi.org/10.7314/APJCP.2014.15.11.4519

p38 MAPK Signaling Mediates Mitochondrial Apoptosis in Cancer Cells Induced by Oleanolic Acid  

Liu, Jia (Institutes of Oceanology, Chinese Academy of Sciences)
Wu, Ning (Institutes of Oceanology, Chinese Academy of Sciences)
Ma, Lei-Na (Department of Molecular Biology, School of Medicine and Pharmacy, Ocean University of China)
Zhong, Jia-Teng (Department of Pathophysiology, Norman Bethune College of Medicine, Jilin University)
Liu, Ge (Institutes of Oceanology, Chinese Academy of Sciences)
Zheng, Lan-Hong (Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences)
Lin, Xiu-Kun (Institutes of Oceanology, Chinese Academy of Sciences)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.15, no.11, 2014 , pp. 4519-4525 More about this Journal
Abstract
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.
Keywords
Oleanolic acid; apoptosis; p38 MAPK; cancer; ROS;
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