The nuclear factor erythroid-2-related factor 2 (Nrf2)–Keap1–ARE pathway, a master regulator of oxidative stress, has emerged as a promising target for cancer therapy. Mutations in NFE2L2, KEAP1 , and related genes have been found in many human cancers, especially lung cancer. These mutations lead to constitutive activation of the Nrf2 pathway, which promotes proliferation of cancer cells and their resistance to chemotherapies. Small molecules that inhibit the Nrf2 pathway are needed to arrest tumor growth and overcome chemoresistance in Nrf2-addicted cancers. Here, we identified a novel small molecule, MSU38225, which can suppress Nrf2 pathway activity. MSU38225 downregulates Nrf2 transcriptional activity and decreases the expression of Nrf2 downstream targets, including NQO1, GCLC, GCLM, AKR1C2, and UGT1A6. MSU38225 strikingly decreases the protein level of Nrf2, which can be blocked by the proteasome inhibitor MG132. Ubiquitination of Nrf2 is enhanced following treatment with MSU38225. By inhibiting production of antioxidants, MSU38225 increases the level of reactive oxygen species (ROS) when cells are stimulated with tert-butyl hydroperoxide (tBHP). MSU38225 also inhibits the growth of human lung cancer cells in both two-dimensional cell culture and soft agar. Cancer cells addicted to Nrf2 are more susceptible to MSU38225 for suppression of cell proliferation. MSU38225 also sensitizes human lung cancer cells to chemotherapies both in vitro and in vivo . Our results suggest that MSU38225 is a novel Nrf2 pathway inhibitor that could potentially serve as an adjuvant therapy to enhance the response to chemotherapies in patients with lung cancer.

中文翻译：

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一种新型 Nrf2 通路抑制剂使 Keap1 突变肺癌细胞对化疗敏感

核因子红细胞 2 相关因子 2 (Nrf2)–Keap1–ARE 通路是氧化应激的主要调节因子，已成为癌症治疗的一个有希望的靶点。NFE2L2、KEAP1 和相关基因的突变已在许多人类癌症中被发现，尤其是肺癌。这些突变导致 Nrf2 通路的组成型激活，从而促进癌细胞增殖及其对化疗的耐药性。需要抑制 Nrf2 通路的小分子来阻止肿瘤生长并克服 Nrf2 成瘾癌症的化学耐药性。在这里，我们鉴定了一种新型小分子 MSU38225，它可以抑制 Nrf2 通路活性。MSU38225 下调 Nrf2 转录活性并降低 Nrf2 下游靶标的表达，包括 NQO1、GCLC、GCLM、AKR1C2 和 UGT1A6。MSU38225 显着降低 Nrf2 的蛋白质水平，这可以被蛋白酶体抑制剂 MG132 阻断。使用 MSU38225 处理后，Nrf2 的泛素化得到增强。通过抑制抗氧化剂的产生，MSU38225 在用叔丁基氢过氧化物 (tBHP) 刺激细胞时会增加活性氧 (ROS) 的水平。MSU38225 还在二维细胞培养物和软琼脂中抑制人肺癌细胞的生长。对 Nrf2 上瘾的癌细胞更容易受到 MSU38225 抑制细胞增殖的影响。MSU38225 还在体外和体内使人肺癌细胞对化学疗法敏感。我们的研究结果表明，MSU38225 是一种新型 Nrf2 通路抑制剂，有可能作为一种辅助疗法来增强肺癌患者对化疗的反应。