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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)
  • Published : 2014.06.15

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.

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