Shivhare Surbhi, Choudhury Subholakshmi, Singh Digvijay, Das Amitava
Department of Applied Biology, Council of Scientific & Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad 500 007, TS, India; Academy of Scientific and Innovative Research, Ghaziabad, UP 201 002, India.
Department of Applied Biology, Council of Scientific & Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad 500 007, TS, India; Academy of Scientific and Innovative Research, Ghaziabad, UP 201 002, India.
Biochim Biophys Acta Mol Cell Res. 2023 Oct;1870(7):119528. doi: 10.1016/j.bbamcr.2023.119528. Epub 2023 Jun 23.
Chemoresistance renders a challenge to the clinics to treat breast cancer patients. Current treatment strategies are effective in mitigating tumor growth but remain largely ineffective against cancer-initiating cells or breast Cancer Stem Cells (CSCs). Epithelial-to-mesenchymal-transition (EMT) regulates breast CSC physiology. Zinc finger E-box binding homeobox 1 (ZEB1) is a key EMT-transcription factor that regulates breast CSC - differentiation and metastasis. However, its potential role in modulating tumor chemoresistance has not yet been fully understood. In-silico analysis revealed a higher ZEB1 expression in breast cancer patients that leads to decreased overall and relapse-free survival. We generated sorted breast CSC with stable ZEB1 overexpression (CD24/CD44GFP-ZEB1) and/or silencing (CD24/CD44ZEB1 shRNA) as well as breast cancer cells with stable ZEB1 overexpression (CD24GFP-ZEB1) and/or silencing (CD24ZEB1 shRNA). An increased colony-forming efficiency and doxorubicin accumulation correlated with decreased promoter activity and expression profile of ABCC1 drug-efflux ABC transporter in CD24/CD44GFP-ZEB1. Additionally, CD24/CD44GFP-ZEB1 demonstrated doxorubicin-induced higher anti-apoptotic and lower pro-apoptotic protein expressions in the mitochondrial and cytosolic fractions. Chemoresistant CD24/CD44GFP-ZEB1 cells depicted 1000-fold higher IC-50 values of doxorubicin and decreased activation of JNK-p38 stress kinase molecular signaling-dependent mammosphere forming efficiency to evade apoptosis. Thus, ZEB1 and its downstream effectors are plausible therapeutic targets for the mitigation of breast cancer chemoresistance in patients.
化疗耐药性给乳腺癌患者的临床治疗带来了挑战。目前的治疗策略在减缓肿瘤生长方面是有效的，但在对抗癌症起始细胞或乳腺癌干细胞（CSCs）方面仍然基本无效。上皮-间质转化（EMT）调节乳腺癌干细胞的生理功能。锌指E盒结合同源框1（ZEB1）是一种关键的EMT转录因子，可调节乳腺癌干细胞的分化和转移。然而，其在调节肿瘤化疗耐药性方面的潜在作用尚未完全明确。计算机分析显示，乳腺癌患者中ZEB1表达较高，这导致总体生存率和无复发生存率降低。我们生成了稳定过表达ZEB1（CD24/CD44GFP-ZEB1）和/或沉默ZEB1（CD24/CD44ZEB1 shRNA）的分选乳腺癌干细胞，以及稳定过表达ZEB1（CD24GFP-ZEB1）和/或沉默ZEB1（CD24ZEB1 shRNA）的乳腺癌细胞。在CD24/CD44GFP-ZEB1中，集落形成效率增加和阿霉素积累与ABCC1药物外排ABC转运蛋白的启动子活性降低和表达谱相关。此外，CD24/CD44GFP-ZEB1在线粒体和胞质部分显示阿霉素诱导的更高抗凋亡蛋白表达和更低促凋亡蛋白表达。化疗耐药的CD24/CD44GFP-ZEB1细胞阿霉素的IC-50值高1000倍，且JNK-p38应激激酶分子信号依赖的乳腺球形成效率激活降低，以逃避凋亡。因此，ZEB1及其下游效应分子可能是减轻患者乳腺癌化疗耐药性的合理治疗靶点。
