双氢青蒿素通过促进 AIM2/caspase-3/DFNA5 轴诱导乳腺癌细胞发生细胞焦亡。

Dihydroartemisinin induces pyroptosis by promoting the AIM2/caspase-3/DFNA5 axis in breast cancer cells.

机构信息

Department of Thyroid and Breast and Vascular Surgery, Renmin Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei Province, PR China.

Department of Otolaryngology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei Province, PR China.

出版信息

Chem Biol Interact. 2021 May 1;340:109434. doi: 10.1016/j.cbi.2021.109434. Epub 2021 Mar 6.

DOI:10.1016/j.cbi.2021.109434

PMID:33689708

Abstract

BACKGROUND

Breast cancer is a complex disease. Recent research has examined the anticancer effects of dihydroartemisinin (DHA) on breast cancer. However, the molecular mechanism of the antitumour effect of DHA is unclear.

METHODS

MCF-7 and MDA-MB-231 cell lines were used for in vitro research. BALB/c nude mice were used to establish breast cancer xenografts. The mRNA and protein levels were analysed by qRT-PCR and western blotting, respectively. Flow cytometry was performed to examine cell apoptosis. ELISA kits were used to evaluate the production of interleukin-1β (IL-1β) and IL-18. LDH and ATP release were individually measured with the corresponding kits. A colony formation assay was used to examine the proliferation of breast cancer cells.

RESULTS

DHA inhibited proliferation and induced pyroptosis in breast cancer cells. Mechanistically, DHA activated the expression of absent in melanoma 2 (AIM2), caspase-3 and gasdermin E (DFNA5). In addition, AIM2 promoted DFNA5 expression by activating caspase-3. Knockdown of AIM2 and DFNA5 significantly enhanced breast cancer cell resistance to DHA. In vivo experiments showed that the tumorigenicity of breast cancer cells was significantly suppressed by DHA. Moreover, the AIM2/caspase-3/DFNA5 axis was activated by DHA and then induced pyroptosis.

CONCLUSIONS

Our findings indicate that DHA inhibits tumorigenesis by inducing pyroptosis in breast cancer cells, highlighting a promising therapeutic strategy for breast cancer.

摘要

背景

乳腺癌是一种复杂的疾病。最近的研究探讨了二氢青蒿素（DHA）对乳腺癌的抗癌作用。然而，DHA 抗肿瘤作用的分子机制尚不清楚。

方法

采用 MCF-7 和 MDA-MB-231 细胞系进行体外研究。使用 BALB/c 裸鼠建立乳腺癌异种移植模型。分别通过 qRT-PCR 和 Western blot 分析 mRNA 和蛋白水平。通过流式细胞术检测细胞凋亡。使用 ELISA 试剂盒评估白细胞介素-1β（IL-1β）和 IL-18 的产生。分别使用相应的试剂盒测量乳酸脱氢酶（LDH）和三磷酸腺苷（ATP）的释放。通过集落形成实验检测乳腺癌细胞的增殖。

结果

DHA 抑制乳腺癌细胞的增殖并诱导其发生细胞焦亡。机制上，DHA 激活了缺失黑色素瘤 2（AIM2）、半胱氨酸蛋白酶-3（caspase-3）和 Gasdermin E（DFNA5）的表达。此外，AIM2 通过激活 caspase-3 促进 DFNA5 的表达。敲低 AIM2 和 DFNA5 可显著增强乳腺癌细胞对 DHA 的耐药性。体内实验表明 DHA 显著抑制了乳腺癌细胞的致瘤性。此外，DHA 激活了 AIM2/caspase-3/DFNA5 轴，进而诱导细胞焦亡。