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

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Tumor Biology

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.

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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.

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    Authors and Affiliations

    1. College of Medicine, Qingdao University, 38 Dengzhou Road, Qingdao, 266021, China

      Jia Liu, Leina Ma, Xiao Chen, Jianxun Wang, Tao Yu, Ying Gong, Aiguo Ma & Hui Liang

    2. The Affiliated Hospital to Qingdao University, Qingdao, 266003, China

      Leina Ma

    3. Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao, 266071, China

      Lanhong Zheng

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    1. Jia Liu
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    2. Leina Ma
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    3. Xiao Chen
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    Correspondence to Lanhong Zheng or Hui Liang.

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    Jia Liu and Leina Ma contributed equally to this work.

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    Liu, J., Ma, L., Chen, X. et al. ERK inhibition sensitizes cancer cells to oleanolic acid-induced apoptosis through ERK/Nrf2/ROS pathway. Tumor Biol. 37, 8181–8187 (2016). https://doi.org/10.1007/s13277-015-4668-4

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    • DOI: https://doi.org/10.1007/s13277-015-4668-4

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