Vitamin D suppresses CD133+/CD44 + cancer stem cell stemness by inhibiting NF-κB signaling and reducing NLRP3 expression in triple-negative breast cancer.

IF 2.7 4区 医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2024-07-01 Epub Date: 2024-03-08 DOI:10.1007/s00280-024-04660-w
Wei Zheng, Wei Peng, Fuyong Qian, Mingshuai Zhang, Bofeng Duan, Zhifeng Fan, Yi Xie, Xiaoying Fu
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Abstract

Background and objective: This study aims to investigate the role of Vitamin D (VD) in regulating the stemness and survival of CD133+/CD44 + breast cancer stem cells, and to explore the role of NLRP3 in this process.

Methods: Breast cancer tissues were collected for RXRα and VDR expression analysis. A triple-negative breast cancer cell line was cultured and stem-like cells (CD133 + CD44+) isolated using flow cytometry. These cells were treated with VD, analyzing their stem-like properties, apoptosis and proliferation, as well as P65 nuclear expression and NLRP3 expression. After NLRP3 inflammasome activator treatment, the parameters were reassessed. RXRα and VDR interaction was confirmed using co-immunoprecipitation (CoIP). Finally, a subcutaneous xenograft model of triple-negative breast cancer was treated with VD and subsequently analyzed for stem-like properties, proliferation, apoptosis, and NLRP3 expression levels.

Results: CD133+/CD44 + stem cells expressed high levels of SOX2 and OCT4. VD treatment resulted in a significant decrease in SOX2 and OCT4 expression, fewer sphere-forming colonies, lower proliferation ability, and more apoptosis. Additionally, VD treatment inhibited NF-κB signaling and reduced NLRP3 expression. The NLRP3 activator BMS-986,299 counteracted the effects of VD in vitro. In vivo, VD inhibited the growth of breast cancer stem cells, reducing both tumor volume and weight, and decreased NLRP3, SOX2, and OCT4 expression within tumor tissues.

Conclusion: Findings elucidate that VD mediates the modulation of stemness in CD133+/CD44 + breast cancer stem cells through the regulation of NLRP3 expression. The research represents novel insights on the implications for the application of VD in cancer therapies.

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维生素D通过抑制三阴性乳腺癌中的NF-κB信号传导和减少NLRP3表达,抑制CD133+/CD44+癌症干细胞的干性。
背景和目的:本研究旨在探讨维生素D(VD)在调控CD133+/CD44+乳腺癌干细胞的干性和存活中的作用,并探索NLRP3在这一过程中的作用:方法:采集乳腺癌组织进行RXRα和VDR表达分析。培养三阴性乳腺癌细胞系,使用流式细胞术分离干样细胞(CD133 + CD44+)。用 VD 处理这些细胞,分析它们的干样特性、凋亡和增殖,以及 P65 核表达和 NLRP3 表达。经 NLRP3 炎性体激活剂处理后,重新评估了这些参数。通过共免疫沉淀(CoIP)确认了RXRα和VDR的相互作用。最后,用 VD 处理了三阴性乳腺癌皮下异种移植模型,随后分析了干样特性、增殖、凋亡和 NLRP3 表达水平:结果:CD133+/CD44+干细胞表达高水平的SOX2和OCT4。VD处理后,SOX2和OCT4的表达明显减少,球形集落减少,增殖能力降低,凋亡增多。此外,VD 处理还抑制了 NF-κB 信号传导,减少了 NLRP3 的表达。NLRP3 激活剂 BMS-986,299 抵消了 VD 在体外的作用。在体内,VD抑制了乳腺癌干细胞的生长,减少了肿瘤体积和重量,并降低了肿瘤组织中NLRP3、SOX2和OCT4的表达:研究结果阐明,VD通过调节NLRP3的表达介导CD133+/CD44+乳腺癌干细胞干性的调节。这项研究为VD在癌症疗法中的应用提供了新的见解。
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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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