Department of Pathology, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-gu, Seoul, 02841, South Korea.
Department of Biomedical Science, Korea University College of Medicine, Seoul, 02841, South Korea.
Sci Rep. 2021 Jan 13;11(1):1247. doi: 10.1038/s41598-021-81021-0.
Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator of several antioxidant and anti-inflammatory enzymes. It binds to its endogenous inhibitor Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm under normal conditions. Various endogenous or environmental oxidative stresses can disrupt the Nrf2/Keap1 complex, allowing Nrf2 to translocate into the nucleus, where it induces the transcription of various cytoprotective enzymes by binding to antioxidant responsive elements. These enzymes have been reported to play a role in regulating tumour growth, angiogenesis, and chemoprevention. Invasion and migration are the most harmful aspects of cancer; they directly impacts the patients' survival. Although the roles of Keap1/Nrf2 and their downstream genes in various cancers have been widely documented, their role in regulating cell motility still remains unclear, particularly in cancer cells. We observed that Nrf2 suppression following treatment with brusatol in non-small-cell lung cancer (NSCLC) cells with either exogenously introduced Keap1 or siNrf2 resulted in the inhibition of cell migration and invasion, with shrinking cell morphology due to decreased focal adhesions via inhibition of the RhoA-ROCK1 pathway. Nrf2 overexpression showed opposite results. Thus, the Nrf2/Keap1 pathway may affect cell motility by dysregulating the RhoA-ROCK1 signalling pathway in NSCLC.
核因子红细胞 2 相关因子 2（Nrf2）是几种抗氧化和抗炎酶的关键转录调节剂。在正常情况下，它在细胞质中与内源性抑制剂 Kelch 样 ECH 相关蛋白 1（Keap1）结合。各种内源性或环境氧化应激可以破坏 Nrf2/Keap1 复合物，使 Nrf2 易位到细胞核内，在那里通过与抗氧化反应元件结合诱导各种细胞保护酶的转录。据报道，这些酶在调节肿瘤生长、血管生成和化学预防方面发挥作用。侵袭和迁移是癌症最具危害性的方面；它们直接影响患者的生存。尽管 Keap1/Nrf2 及其下游基因在各种癌症中的作用已被广泛记录，但它们在调节细胞运动中的作用仍不清楚，特别是在癌细胞中。我们观察到，在用 brusatol 处理非小细胞肺癌（NSCLC）细胞时，抑制 Nrf2 的表达，无论是通过外源性引入 Keap1 还是 siNrf2，都会抑制细胞迁移和侵袭，由于 RhoA-ROCK1 通路的抑制导致细胞形态缩小，黏着斑减少。Nrf2 的过表达则显示出相反的结果。因此，Nrf2/Keap1 通路可能通过调节 NSCLC 中的 RhoA-ROCK1 信号通路来影响细胞运动。
