他莫昔芬通过NRF2介导的乳腺癌代谢重编程诱导放射抗性

IF 6 3区 医学 Q1 CELL BIOLOGY
F V Reinema, F C G J Sweep, G J Adema, W J M Peeters, J W M Martens, J Bussink, P N Span
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引用次数: 0

摘要

背景:最近,我们报道了他莫昔芬耐药(TAM-R)乳腺癌细胞对辐照具有交叉耐药性。在此,我们研究了他莫昔芬诱导放射抗性的相关机制,旨在预防或逆转抗性,改善乳腺癌治疗:方法:使用 Seahorse 代谢分析仪分析野生型 ERα 阳性 MCF7 和 ERα 阴性 MDA-MB-231 乳腺癌细胞及其 TAM-R 对应细胞的细胞代谢。还测定了实时 ROS 生成、毒性以及对 H2O2、他莫昔芬和辐照的抗氧化能力。对 28 名乳腺癌患者短期手术前他莫昔芬治疗前后的肿瘤材料(ClinicalTrials.gov Identifier:NCT00738777,2008 年 8 月 19 日)和细胞材料进行了 NRF2 基因表达和免疫组化分析。通过药理抑制作用确定了 TAM-R 细胞对辐照的再敏感性:结果:TAM-R细胞的耗氧量降低,糖酵解增加,表明线粒体功能障碍。然而,这并不能解释放射抗性,因为没有线粒体的细胞(Rho-0)实际上对放射更敏感。他莫昔芬和 H2O2 暴露后的实时 ROS 测量表明,TAM-R 细胞的 ROS 水平和毒性较低。同样,TAM-R 细胞中的抗氧化剂水平也更高,从而提供了对辐照诱导的 ROS 的保护。抗氧化反应的主要激活剂 NRF2 在 TAM-R 细胞和接受短期术前他莫昔芬治疗的患者的肿瘤组织中有所增加。抑制NRF2可使TAM-R细胞对辐照重新敏感:结论:他莫昔芬诱导放射抗性的机制与细胞对持续增加的 ROS 水平的适应有关,这导致细胞的抗氧化能力和糖酵解能力长期处于上调状态。药物抑制抗氧化反应可使乳腺癌细胞对辐照重新敏感。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Tamoxifen induces radioresistance through NRF2-mediated metabolic reprogramming in breast cancer.

Tamoxifen induces radioresistance through NRF2-mediated metabolic reprogramming in breast cancer.

Tamoxifen induces radioresistance through NRF2-mediated metabolic reprogramming in breast cancer.

Tamoxifen induces radioresistance through NRF2-mediated metabolic reprogramming in breast cancer.

Background: Recently, we reported that tamoxifen-resistant (TAM-R) breast cancer cells are cross-resistant to irradiation. Here, we investigated the mechanisms associated with tamoxifen-induced radioresistance, aiming to prevent or reverse resistance and improve breast cancer treatment.

Methods: Wild-type ERα-positive MCF7 and ERα-negative MDA-MB-231 breast cancer cells and their TAM-R counterparts were analyzed for cellular metabolism using the Seahorse metabolic analyzer. Real-time ROS production, toxicity, and antioxidant capacity in response to H2O2, tamoxifen, and irradiation were determined. Tumor material from 28 breast cancer patients before and after short-term presurgical tamoxifen (ClinicalTrials.gov Identifier: NCT00738777, August 19, 2008) and cellular material was analyzed for NRF2 gene expression and immunohistochemistry. Re-sensitization of TAM-R cells to irradiation was established using pharmacological inhibition.

Results: TAM-R cells exhibited decreased oxygen consumption and increased glycolysis, suggesting mitochondrial dysfunction. However, this did not explain radioresistance, as cells without mitochondria (Rho-0) were actually more radiosensitive. Real-time measurement of ROS after tamoxifen and H2O2 exposure indicated lower ROS levels and toxicity in TAM-R cells. Consistently, higher antioxidant levels were found in TAM-R cells, providing protection from irradiation-induced ROS. NRF2, a main activator of the antioxidant response, was increased in TAM-R cells and in tumor tissue of patients treated with short-term presurgical tamoxifen. NRF2 inhibition re-sensitized TAM-R cells to irradiation.

Conclusion: Mechanisms underlying tamoxifen-induced radioresistance are linked to cellular adaptations to persistently increased ROS levels, leading to cells with chronically upregulated antioxidant capacity and glycolysis. Pharmacological inhibition of antioxidant responses re-sensitizes breast cancer cells to irradiation.

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来源期刊
自引率
1.70%
发文量
17
审稿时长
14 weeks
期刊介绍: Cancer & Metabolism welcomes studies on all aspects of the relationship between cancer and metabolism, including: -Molecular biology and genetics of cancer metabolism -Whole-body metabolism, including diabetes and obesity, in relation to cancer -Metabolomics in relation to cancer; -Metabolism-based imaging -Preclinical and clinical studies of metabolism-related cancer therapies.
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