Combined inhibition of autophagy and Nrf2 signaling augments bortezomib-induced apoptosis by increasing ROS production and ER stress in pancreatic cancer cells.
Combined inhibition of autophagy and Nrf2 signaling augments bortezomib-induced apoptosis by increasing ROS production and ER stress in pancreatic cancer cells.
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自噬和 Nrf2 信号传导的联合抑制通过增加胰腺癌细胞中 ROS 的产生和 ER 应激来增强硼替佐米诱导的细胞凋亡
DOI：
10.7150/ijbs.26776
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发表时间：
2018
影响因子：
9.2
通讯作者：
Qin R
中科院分区：
文献类型：
--
作者：
Li X;Liang M;Jiang J;He R;Wang M;Guo X;Shen M;Qin R
胰腺癌（PC）对目前的治疗具有高度耐药性;因此，迫切需要开发新的治疗策略。蛋白酶体对于参与细胞增殖和存活的蛋白质稳态至关重要，使其成为癌症中有吸引力的治疗靶点。然而，最近的研究表明，硼替佐米，一种高度选择性的蛋白酶体抑制剂，在实体瘤包括PC中的作用有限。因此，迫切需要对硼替佐米的化学增敏策略进行更多的机理研究。在此，我们证明硼替佐米通过涉及PC细胞中内质网（ER）应激的机制诱导细胞凋亡和自噬。此外，硼替佐米治疗导致细胞内活性氧（ROS）水平增加，这在硼替佐米诱导的ER应激和细胞凋亡中起关键作用。此外，自噬作为一种补偿机制，以消除硼替佐米诱导的ROS和抵抗ER应激介导的细胞凋亡。此外，Nrf 2介导的抗氧化反应，其对抗硼替佐米诱导的自噬，也保护细胞免受硼替佐米诱导的ROS产生。最后，自噬和Nrf 2信号的双重抑制通过升高ROS水平和ER应激协同增强硼替佐米诱导的细胞凋亡。总之，这些数据表明，自噬和Nrf 2抗氧化系统的激活，降低细胞内ROS，是PC细胞克服硼替佐米治疗的机制。总之，将蛋白酶体抑制剂与靶向自噬和Nrf 2信号传导的药物组合可能是PC治疗的有希望的治疗方法。
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.
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