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Tumor Biology

, Volume 37, Issue 6, pp 8181–8187 | Cite as

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

  • Jia Liu
  • Leina Ma
  • Xiao Chen
  • Jianxun Wang
  • Tao Yu
  • Ying Gong
  • Aiguo Ma
  • Lanhong Zheng
  • Hui Liang
Original Article

Abstract

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.

Keywords

Oleanolic acid Apoptosis ERK Nrf2 

Notes

Acknowledgments

This work was supported by funds from National Natural Sciences Foundation of China (nos. 81502065, 81573137, and 31501142), China Postdoctoral Science Foundation Funded Project (2015M580574), Natural Sciences Foundation of Shandong Province (ZR2014HQ009), Special Scientific Research Funds for Central Non-profit Institutes, Chinese Academy of Fishery Sciences (2014B01YQ01), 863 High Technology Project (No. 2014AA093503), and Young Teacher Training Program for Innovation Team in Medical College of Qingdao University.

Compliance with ethical standards

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Jia Liu
    • 1
  • Leina Ma
    • 1
    • 2
  • Xiao Chen
    • 1
  • Jianxun Wang
    • 1
  • Tao Yu
    • 1
  • Ying Gong
    • 1
  • Aiguo Ma
    • 1
  • Lanhong Zheng
    • 3
  • Hui Liang
    • 1
  1. 1.College of MedicineQingdao UniversityQingdaoChina
  2. 2.The Affiliated Hospital to Qingdao UniversityQingdaoChina
  3. 3.Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery SciencesQingdaoChina

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