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Int J Biol Sci 2018; 14(10):1291-1305. doi:10.7150/ijbs.26776

Research Paper

Combined inhibition of autophagy and Nrf2 signaling augments bortezomib-induced apoptosis by increasing ROS production and ER stress in pancreatic cancer cells

Xu Li1,*, Meng Liang2,*, Jianxin Jiang3, Ruizhi He1, Min Wang1, Xingjun Guo1,✉, Ming Shen1,✉, Renyi Qin1,✉

1. Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
2. Department of Hepatobiliary Surgery, Affiliated Hospital of Hebei University, Baoding, Hebei, China
3. Department of Hepatic-Biliary-Pancreatic Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
*These authors contributed equally to this work.

Abstract

Pancreatic cancer (PC) is highly resistant to current therapies; thus, there is an urgent need to develop new treatment strategies. The proteasome is crucially important for proteostasis, which is involved in cell proliferation and survival, making it an attractive therapeutic target in cancer. However, recent studies have indicated that bortezomib, a highly selective proteasome inhibitor, has limited effects in solid tumors including PC. Thus, more mechanistic insights into chemo-sensitization strategies for bortezomib are urgently needed. Herein, we demonstrate that bortezomib induced apoptosis and autophagy via a mechanism involving endoplasmic reticulum (ER) stress in PC cells. Additionally, bortezomib treatment led to increased levels of intracellular reactive oxygen species (ROS), which play critical roles in bortezomib-induced ER stress and apoptosis. Moreover, autophagy functions as a compensatory mechanism to eliminate bortezomib-induced ROS and resists ER stress-mediated apoptosis. Additionally, the Nrf2-mediated antioxidative response, which works against with bortezomib-induced autophagy, also protected cells against bortezomib-induced ROS production. Finally, the dual inhibition of autophagy and Nrf2 signaling cooperatively enhanced bortezomib-induced apoptosis by elevating ROS levels and ER stress. Together, these data demonstrate that activation of autophagy and the Nrf2 antioxidant system, which lowers intracellular ROS, are mechanistically how PC cells overcome bortezomib treatment. In summary, combining proteasome inhibitors with drugs targeting autophagy and Nrf2 signaling could be a promising therapeutic approach for PC treatment.

Keywords: Autophagy, Nrf2, Pancreatic cancer, Bortezomib, ROS, ER stress

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How to cite this article:
Li X, Liang M, Jiang J, He R, Wang M, Guo X, Shen M, Qin R. Combined inhibition of autophagy and Nrf2 signaling augments bortezomib-induced apoptosis by increasing ROS production and ER stress in pancreatic cancer cells. Int J Biol Sci 2018; 14(10):1291-1305. doi:10.7150/ijbs.26776. Available from http://www.ijbs.com/v14p1291.htm