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FUT4siRNA 通过激活 FOXO1 诱导的细胞凋亡增强非小细胞肺癌对顺铂的化疗敏感性。

FUT4siRNA augments the chemosensitivity of non-small cell lung cancer to cisplatin through activation of FOXO1-induced apoptosis.

机构信息

Department of Clinical Medicine, Zhejiang University City College School of Medicine, 50 Huzhou Road, Hangzhou, 310015, P.R. China.

Department of Toracic Surgery, Zhejiang Cancer Hospital, Hangzhou, 310000, China.

出版信息

BMC Cancer. 2020 Sep 18;20(1):895. doi: 10.1186/s12885-020-07324-z.

Abstract

BACKGROUND

Increased fucosylation is associated with the chemoresistance phenotype. Meanwhile, fucosyltransferase IV (FUT4) amounts are frequently elevated in lung cancer and may be related to increased chemoresistance.

METHODS

In the present work, FUT4's role in cisplatin-induced apoptosis was assessed in A549 and H1975 cells, respectively. To clarify whether the FUT4 gene attenuates chemosensitivity in tumor cells, we constructed FUT4siRNA and evaluated its effects on cisplatin-induced apoptosis and cell growth inhibition. Cell viability, apoptosis, migration and invasion assay were conducted to investigate cisplatin sensitivity. The activation of EGFR/AKT/FOXO1 signaling were measured by western blot. The translocation of FOXO1 was assessed by IFC using Laser Scanning Confocal Microscope.

RESULTS

We found that FUT4 knockdown dose-dependently increased cisplatin-associated cytotoxicity. Furthermore, FUT4 silencing induced apoptosis and inhibited proliferation in A549 and H1975 cells by suppressing Akt and FOXO1 phosphorylation induced by cisplatin administration, which resulted in nuclear translocation of FOXO1.

CONCLUSION

These results suggested FUT4 might control chemoresistance to cisplatin in lung cancer by suppressing FOXO1-induced apoptosis.

摘要

背景

岩藻糖基化增加与化疗耐药表型有关。同时,肺癌中 fucosyltransferase IV (FUT4) 的含量经常升高,这可能与化疗耐药性增加有关。

方法

在本研究中,分别在 A549 和 H1975 细胞中评估了 FUT4 在顺铂诱导的细胞凋亡中的作用。为了阐明 FUT4 基因是否会降低肿瘤细胞的化疗敏感性,我们构建了 FUT4siRNA,并评估了其对顺铂诱导的细胞凋亡和细胞生长抑制的影响。通过细胞活力、凋亡、迁移和侵袭试验来研究顺铂敏感性。通过 Western blot 测定 EGFR/AKT/FOXO1 信号通路的激活。通过激光共聚焦显微镜的 IFC 评估 FOXO1 的易位。

结果

我们发现 FUT4 敲低可剂量依赖性地增加顺铂相关的细胞毒性。此外,FUT4 沉默通过抑制顺铂给药诱导的 Akt 和 FOXO1 磷酸化,抑制 A549 和 H1975 细胞中的增殖并诱导细胞凋亡,导致 FOXO1 核易位。

结论

这些结果表明,FUT4 可能通过抑制 FOXO1 诱导的凋亡来控制肺癌对顺铂的化疗耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/147a/7501616/d33710bce83a/12885_2020_7324_Fig1_HTML.jpg

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