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Xanthatin 通过 JAK2/STAT4/BARD1 轴与顺铂协同作用抑制人非小细胞肺癌细胞中的同源重组。

Xanthatin synergizes with cisplatin to suppress homologous recombination through JAK2/STAT4/BARD1 axis in human NSCLC cells.

机构信息

Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.

出版信息

J Cell Mol Med. 2021 Feb;25(3):1688-1699. doi: 10.1111/jcmm.16271. Epub 2021 Jan 13.

DOI:10.1111/jcmm.16271
PMID:33439503
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7875932/
Abstract

Xanthatin (Xa) is a bicyclic sesquiterpene lactone identified from the plant Xanthium L. with impressive antitumor activity, but the role of Xa in non-small cell lung cancer (NSCLC) is not known. Here we found that Xa inhibits proliferation, migration, invasion and induces apoptosis in NSCLC cells. RNA sequencing and Gene set enrichment analysis revealed that Xa significantly activates p53 pathway and suppresses E2F targets, G2M checkpoint and MYC targets in A549 cells. Among these changed genes, the down-regulated gene BARD1 triggered by Xa was identified as a candidate involved in Xa's antitumor effect because of its vital role in homologous recombination (HR). Further studies demonstrated that Xa inhibits HR through the BARD1/BRCA1/RAD51 axis, which enhances cell sensitivity to cisplatin. Mechanistic studies showed that Xa inhibits BARD1 through the JAK2/STAT4 pathway. Our study revealed that Xa is a promising drug to treat NSCLC, especially in combination with conventional chemotherapy.

摘要

旋覆花内酯（Xa）是一种从菊科植物旋覆花中鉴定出来的双环倍半萜内酯，具有显著的抗肿瘤活性，但 Xa 在非小细胞肺癌（NSCLC）中的作用尚不清楚。在这里，我们发现 Xa 能抑制 NSCLC 细胞的增殖、迁移和侵袭，并诱导其凋亡。RNA 测序和基因集富集分析显示，Xa 能显著激活 A549 细胞中的 p53 通路，并抑制 E2F 靶点、G2M 检查点和 MYC 靶点。在这些变化的基因中，Xa 下调的 BARD1 基因被鉴定为参与 Xa 抗肿瘤作用的候选基因，因为它在同源重组（HR）中起着至关重要的作用。进一步的研究表明，Xa 通过 BARD1/BRCA1/RAD51 轴抑制 HR，从而增强细胞对顺铂的敏感性。机制研究表明，Xa 通过 JAK2/STAT4 通路抑制 BARD1。我们的研究表明，Xa 是一种有前途的治疗 NSCLC 的药物，特别是与传统化疗联合使用时。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2f/7875932/c584e555c913/JCMM-25-1688-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2f/7875932/584c27f424b1/JCMM-25-1688-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2f/7875932/fcb14d511678/JCMM-25-1688-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2f/7875932/3be9eac349d3/JCMM-25-1688-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2f/7875932/efcc690fab69/JCMM-25-1688-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2f/7875932/151ea55bc819/JCMM-25-1688-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2f/7875932/c584e555c913/JCMM-25-1688-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2f/7875932/584c27f424b1/JCMM-25-1688-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2f/7875932/fcb14d511678/JCMM-25-1688-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2f/7875932/3be9eac349d3/JCMM-25-1688-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2f/7875932/efcc690fab69/JCMM-25-1688-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2f/7875932/151ea55bc819/JCMM-25-1688-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2f/7875932/c584e555c913/JCMM-25-1688-g007.jpg

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