Continuous exposure to doxorubicin induces stem cell-like characteristics and plasticity in MDA-MB-231 breast cancer cells identified with the SORE6 reporter.

IF 2.7 4区 医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2024-10-01 Epub Date: 2024-08-24 DOI:10.1007/s00280-024-04701-4
Nohemí Salinas-Jazmín, María Adriana Medina-Mondragón, Jeannie Jiménez-López, Sandra Lucia Guerrero-Rodríguez, Patricia Cuautle-Rodríguez, Marco Antonio Velasco-Velázquez
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Abstract

Purpose: Cancer stem cells (CSCs) account for recurrence and resistance to breast cancer drugs, rendering them a cause of mortality and therapeutic failure. In this study, we examined the effects of exposure to low concentrations of doxorubicin (Dox) on CSCs and non-CSCs from TNBC.

Methods: The effects of Dox were studied using the SORE6 reporter system. We examined the enrichment of the CSCs population, as well as the proliferation, and death of the reporter-positive fraction (GFP + cells) by flow cytometry. The resistant and stemness phenotypes were analyzed by viability and mammosphere formation assay, respectively. We identified differentially expressed and coregulated genes by RNA-seq analysis, and the correlation between gene expression and clinical outcome was evaluated by Kaplan-Mayer analysis using public databases.

Results: In MDAMB231 and Hs578t cells, we identified enriched subsets in the CSCs population after continuous exposure to low concentrations of Dox. Cells from these enriched cultures showed resistance to toxic concentrations of Dox and increased efficiency of mammosphere formation. In purified GFP + or GFP- cells, Dox increased the mammosphere-forming efficiency, promoted phenotypic switches in non-CSCs populations to a CSC-like state, reduced proliferation, and induced differential gene expression. We identified several biological processes and molecular functions that partially explain the development of doxorubicin-resistant cells and cellular plasticity. Among the genes that were regulated by Dox exposure, the expression of ITGB1, SNAI1, NOTCH4, STAT5B, RAPGEF3, LAMA2, and GNAI1 was significantly associated with poor survival, the stemness phenotype, and chemoresistance.

Conclusion: The generation of chemoresistant cells that have characteristics of CSCs, after exposure to low concentrations of Dox, involves the differential expression of genes that have a clinical impact.

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持续暴露于多柔比星可诱导 MDA-MB-231 乳腺癌细胞的干细胞样特征和可塑性,并通过 SORE6 报告器进行鉴定。
目的:癌症干细胞(CSCs)是乳腺癌复发和耐药的原因之一,也是导致死亡和治疗失败的原因之一。在这项研究中,我们考察了暴露于低浓度多柔比星(Dox)对 TNBC 的癌干细胞和非癌干细胞的影响:方法:我们使用 SORE6 报告系统研究了 Dox 的影响。我们通过流式细胞术检测了CSCs群体的富集以及报告基因阳性部分(GFP +细胞)的增殖和死亡。抗性和干性表型分别通过存活率和乳球形成试验进行了分析。我们通过RNA-seq分析确定了差异表达基因和核心配对基因,并利用公共数据库通过Kaplan-Mayer分析评估了基因表达与临床结果之间的相关性:结果:在MDAMB231和Hs578t细胞中,我们发现了持续暴露于低浓度Dox后CSCs群体中的富集亚群。来自这些富集培养物的细胞表现出对毒性浓度Dox的耐受性,并提高了乳球形成的效率。在纯化的 GFP + 或 GFP- 细胞中,Dox 提高了乳腺小球形成的效率,促进了非 CSCs 群体向 CSC 样状态的表型转换,减少了增殖,并诱导了不同的基因表达。我们发现了一些生物过程和分子功能,它们部分解释了多柔比星耐药细胞的发育和细胞可塑性。在受Dox暴露调控的基因中,ITGB1、SNAI1、NOTCH4、STAT5B、RAPGEF3、LAMA2和GNAI1的表达与存活率低、干性表型和化疗耐药性显著相关:结论:暴露于低浓度Dox后,具有CSCs特征的化疗耐药细胞的生成涉及对临床有影响的基因的差异表达。
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来源期刊
CiteScore
6.10
自引率
3.30%
发文量
116
审稿时长
2.5 months
期刊介绍: Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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