Anthraflavic Acid Exerts Antimetastatic Effects on Human Non-Small-cell Lung Cancer Cells Via Activation of Aryl Hydrocarbon Receptor and Regulation of the JNK, p38, and c-myc Signaling Pathways

초록

Matrix metalloproteinases can degrade major extracellular matrix (ECM) components, thereby contributing to cancer metastasis. Reactive oxygen species (ROS) are closely related to the regulation of cancer metastasis. Here, we report that the polycyclic aromatic hydrocarbon compound anthraflavic acid (AFA), a derivative of anthraquinone, exerts an antimetastatic effect on human non-small-cell lung cancer (NSCLC) cells via ROS regulation. Molecular docking analysis indicated that AFA is a potential agonist for aryl hydrocarbon receptor (AHR). AFA stimulates transcriptional expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and reduces ROS level via AHR. AFA inhibits the cell migration/invasion and transcriptional expression of MMP-2 and MMP-9, two major gelatinases that can degrade gelatin, which is a major ECM component. The antimetastatic effects of AFA on A549 human NSCLC cells were reversed by hydrogen peroxide. This implies that the AFA exerts antimetastatic effects through ROS regulation via AHR-Nrf2. AFA also modulates p38, JNK, and c-myc signalings, which are closely related to cancer metastasis regulation. Our results suggest that AFA is a novel effective potential antimetastatic agent for patients with NSCLC.

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