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芳香胺 N-乙酰基转移酶 1 缺乏抑制乳腺癌细胞中药物诱导的细胞死亡：从细胞色素 C 依赖性细胞凋亡向细胞坏死的转变。

Arylamine N-acetyltransferase 1 deficiency inhibits drug-induced cell death in breast cancer cells: switch from cytochrome C-dependent apoptosis to necroptosis.

机构信息

School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia.

出版信息

Breast Cancer Res Treat. 2022 Oct;195(3):223-236. doi: 10.1007/s10549-022-06668-3. Epub 2022 Aug 2.

DOI:10.1007/s10549-022-06668-3
PMID:35918499
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9464750/
Abstract

PURPOSE

Arylamine N-acetyltransferase 1 (NAT1) deficiency has been associated with drug resistance and poor outcomes in breast cancer patients. The current study aimed to investigate drug resistance in vitro using normal breast cancer cell lines and NAT1-deficient cell lines to understand the changes induced by the lack of NAT1 that resulted in poor drug response.

METHODS

The response to seven chemotherapeutic agents was quantified following NAT1 deletion using CRISPR-Cas 9 in MDA-MB-231 and T-47D cells. Apoptosis was monitored by annexin V staining and caspase 3/7 activity. Cytochrome C release and caspase 8 and 9 activities were measured by Western blots. Caspase 8 was inhibited using Z-IETD-FMK and necroptosis was inhibited using necrostatin and necrosulfonamide.

RESULTS

Compared to parental cells, NAT1 depleted cells were resistant to drug treatment. This could be reversed following NAT1 rescue of the NAT1 deleted cells. Release of cytochrome C in response to treatment was decreased in the NAT1 depleted cells, suggesting suppression of the intrinsic apoptotic pathway. In addition, NAT1 knockout resulted in a decrease in caspase 8 activation. Treatment with necrosulfonamide showed that NAT1 deficient cells switched from intrinsic apoptosis to necroptosis when treated with the anti-cancer drug cisplatin.

CONCLUSIONS

NAT1 deficiency can switch cell death from apoptosis to necroptosis resulting in decreased response to cytotoxic drugs. The absence of NAT1 in patient tumours may be a useful biomarker for selecting alternative treatments in a subset of breast cancer patients.

摘要

目的

芳香胺 N-乙酰基转移酶 1（NAT1）缺陷与乳腺癌患者的耐药性和不良预后相关。本研究旨在使用正常乳腺癌细胞系和 NAT1 缺陷细胞系进行体外药物耐药性研究，以了解由 NAT1 缺乏引起的导致药物反应不良的变化。

方法

使用 CRISPR-Cas9 在 MDA-MB-231 和 T-47D 细胞中敲除 NAT1，定量测定七种化疗药物的反应。通过 Annexin V 染色和 caspase 3/7 活性监测细胞凋亡。通过 Western blot 测量细胞色素 C 释放以及 caspase 8 和 9 的活性。使用 Z-IETD-FMK 抑制 caspase 8，使用 necrostatin 和 necrosulfonamide 抑制坏死性凋亡。

结果

与亲本细胞相比，NAT1 耗尽的细胞对药物治疗具有抗性。在用 NAT1 拯救 NAT1 缺失的细胞后，这种抗性可以逆转。NAT1 耗尽的细胞对治疗的细胞色素 C 释放减少，表明抑制了内在凋亡途径。此外，NAT1 敲除导致 caspase 8 激活减少。用 necrosulfonamide 处理表明，当用抗癌药物顺铂处理时，NAT1 缺陷细胞从内在凋亡切换到坏死性凋亡。

结论

NAT1 缺乏可将细胞死亡从凋亡切换到坏死性凋亡，从而导致对细胞毒性药物的反应降低。肿瘤中 NAT1 的缺失可能是选择乳腺癌患者亚组中替代治疗的有用生物标志物。

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