姜黄素激活ROS/KEAP1等的级联反应抑制结直肠癌转移

Curcumin activates a ROS/KEAP1/NRF2/miR-34a/b/c cascade to suppress colorectal cancer metastasis

Chunfeng Liu 1, Matjaz Rokavec 1, Zekai Huang 1, Heiko Hermeking 2 3

Cell Death Differ.( IF 12.067) Pubdate: 2023.5.20

DOI: 10.1038/s41418-023-01178-1.

Abstract:

Curcumin, a natural phytochemical isolated from tumeric roots, represents a candidate for prevention and therapy of colorectal cancer/CRC. However, the exact mechanism of action and the downstream mediators of curcumin's tumor suppressive effects have remained largely unknown. Here we used a genetic approach to determine the role of the p53/miR-34 pathway as mediator of the effects of curcumin. Three isogenic CRC cell lines rendered deficient for the p53, miR-34a and/or miR-34b/c genes were exposed to curcumin and subjected to cell biological analyses. siRNA-mediated inhibition and ectopic expression of NRF2, as well as Western blot, qPCR and qChIP analyses of its target genes were performed. CRC cells were i.v. injected into NOD/SCID mice and lung-metastases formation was determined by longitudinal, non-invasive imaging. In CRC cells curcumin induced apoptosis and senescence, and suppressed migration and invasion in a p53-independent manner. Curcumin activated the KEAP1/NRF2/ARE pathway by inducing ROS. Notably, curcumin induced miR-34a and miR-34b/c expression in a ROS/NRF2-dependent and p53-independent manner. NRF2 directly induced miR-34a and miR-34b/c via occupying multiple ARE motifs in their promoter regions. Curcumin reverted repression of miR-34a and miR-34b/c induced by IL6 and hypoxia. Deletion of miR-34a and miR-34b/c significantly reduced curcumin-induced apoptosis and senescence, and prevented the inhibition of migration and invasion by curcumin or ectopic NRF2. In CRC cells curcumin induced MET and prevented the formation of lung-metastases in mice in a miR-34a-dependent manner. In addition, we found that curcumin may enhance the therapeutic effects of 5-FU on CRC cells deficient for p53 and miR-34a/b/c. Activation of the KEAP1/NRF2/miR-34a/b/c axis mediates the tumor suppressive activity of curcumin and suggests a new approach for activating miR-34 genes in tumors for therapeutic purposes.

推荐理由：

1、研究背景

结直肠癌（CRC）是最致命的癌症之一，需要新的方法和药来改善CRC的预后和治疗。姜黄素是一种多酚，来源于姜黄的根茎，一直是东方美食中流行的食品添加剂，具有作为CRC预防和治疗剂的潜力，在FOLFOX化疗（叶酸/5-氟尿嘧啶/奥沙利铂）的基础上，每日加用口服姜黄素可显著延长转移性结直肠癌患者的无进展生存期和总生存期。在家族性腺瘤性息肉病/FAP患者中，姜黄素和槲皮素联合用药可减少回肠和直肠腺瘤的数量和大小。姜黄素亦被证明会影响CRC细胞中非编码RNA的表达。

2、研究结果

研究发现姜黄素能抑制细胞活力、增殖、迁移和侵袭能力，它通过p53非依赖性方式诱导CRC细胞的凋亡和衰老。姜黄素通过诱导CRC细胞中的ROS激活NRF2，并且在CRC细胞系中以p53非依赖性和ROS依赖性的方式诱导miR-34a和miR-34b/c表达。NRF2介导的miR34a和miR-34b/c miR-8a能介导衰老和凋亡，还能抑制姜黄素处理后CRC细胞的迁移，侵袭和转移。这些结果确立了ROS/KEAP1/NRF2/miR-34a/b/c轴在介导姜黄素肿瘤抑制作用中的核心作用。并且miR-34a/b/c不仅被姜黄素诱导，而且被H2O2和tBHP以NRF2依赖的方式诱导。姜黄素诱导MET并通过诱导miR-34a抑制肺转移的形成。姜黄素还可以增强5-FU对CRC细胞的治疗效果。这种效应在缺乏p53和miR-34a/b/c的细胞中最为明显。

3、研究意义

一项I期临床研究表明，在转移性结直肠癌患者中，在FOLFOX治疗中添加姜黄素是安全且可耐受的，剂量高达2 g。此外，口服高达3600mg姜黄素会导致人结直肠粘膜中的姜黄素浓度在该研究中使用的浓度范围内。研究结果可用于开发恢复p53 / miR-34通路的肿瘤抑制功能的治疗方法。

注：本文转自黄朝晖课题组

转自：“如沐风科研”微信公众号

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