Abstract

Tumors adapt well to the imbalanced redox status created by rapid growth and limited nutrient availability because they highly express high levels of NRF2 to counteract oxidative stress. Therefore, inhibition of NRF2 is currently considered a feasible strategy for development of chemotherapeutic agents. In the present study, we identified that Na⁺/K⁺-ATPase regulates NRF2 in A549 cells. Suppression of Na⁺/K⁺-ATPase by convallatoxin or siRNAs downregulates NRF2 in A549 cells, and this event is mediated by Ca²⁺-dependent induction of CSK1 and subsequent phosphorylation of SRC at Tyr 527. Consistent with this finding, knocking down the α1 or β1 subunit of Na⁺/K⁺-ATPase promotes the generation of intracellular ROS by cisplatin and potentiates cisplatin-induced apoptosis and autophagy in A549 cells. Our study reveals that the signaling axis composed of Na⁺/K⁺-ATPase, CSK1, and tyrosine phosphorylation of Src could be a useful target for development of NRF2 inhibitors.

摘要

肿瘤能够很好地适应由快速生长和有限的营养供应造成的不平衡氧化还原状态，因为它们高度表达高水平的 NRF2 以抵消氧化应激。因此，目前认为抑制 NRF2 是开发化疗药物的可行策略。在本研究中，我们发现 Na ⁺ /K ⁺ -ATPase 调节 A549 细胞中的 NRF2。通过 convallatoxin 或 siRNA抑制 Na ⁺ /K ⁺ -ATPase 会下调 A549 细胞中的 NRF2，并且该事件是由 Ca ²⁺依赖的 CSK1 诱导和随后在 Tyr 527 处的 SRC 磷酸化介导的。与这一发现一致，击倒了Na ⁺ /K ^{+ 的}α1或β1亚基-ATPase 通过顺铂促进细胞内 ROS 的产生，并增强顺铂诱导的 A549 细胞凋亡和自噬。我们的研究表明，由 Na ⁺ /K ⁺ -ATPase、CSK1 和 Src 的酪氨酸磷酸化组成的信号轴可能是开发 NRF2 抑制剂的有用目标。