PO.ET03.01 · 实验与分子治疗
Nrf2在调控山奈酚对三阴性乳腺癌细胞中CDKs、PD-L-1、CCL2和TGM2抑制作用中的角色
Nrf2 role in regulating kaempferol's inhibitory action on CDKs, PD-L-1, CCL2, and TGM2 in triple-negative breast cancer cells
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
三阴性乳腺癌(TNBC)是最具侵袭性的乳腺癌类型之一,其特征为进展迅速、高复发率和治疗选择有限。新出现的证据表明,氧化应激信号传导和肿瘤免疫微环境(TIME)均参与TNBC的治疗耐药。山奈酚(kaempferol)是一种天然存在于水果和蔬菜中的黄酮类化合物,已显示出作为多靶点抗癌化合物的前景,但其作用机制仍未完全阐明。在本研究中,我们探讨了山奈酚如何在两种遗传背景不同的TNBC细胞系MDA-MB-231(白种人)和MDA-MB-468(非裔美国人)中调控肿瘤生长、免疫检查点活性和炎症介质。结果显示,山奈酚通过抑制CDK1、CDK4、CDK6和CDK7的表达,显著降低细胞活力和增殖,诱导凋亡,并导致S期细胞周期阻滞。在细胞因子刺激下,山奈酚通过抑制JAK1/STAT3通路下调IFN-gamma诱导的PD-L1,并减少TNF-alpha诱导的CCL2表达,表明其具有广泛的免疫调节活性。为了解氧化还原调控的作用,我们使用Nrf2 siRNA沉默了转录因子Nrf2(NFE2L2)。有趣的是,Nrf2敲低并未改变山奈酚对PD-L1的抑制,表明PD-L1的调控独立于Nrf2。相反,沉默Nrf2显著增加了CCL2和转谷氨酰胺酶-2(TGM2)的表达,证实了Nrf2在炎症信号传导中的抑制性作用。山奈酚处理逆转了这些增加,使CCL2和TGM2水平回落至接近基线。总之,这些发现凸显了山奈酚通过不同的、Nrf2依赖性和非依赖性通路同时调控免疫检查点和炎症介质的双重能力。结论:本研究阐述了山奈酚通过多种分子机制和靶点发挥的抗癌作用,这可能有助于开发针对TNBC的更有效辅助疗法。
查看英文原文 English abstract
Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer, marked by rapid progression, high recurrence, and limited treatment options. Emerging evidence suggests that both oxidative stress signaling and the tumor immune microenvironment (TIME) contribute to therapy resistance in TNBC. Kaempferol, a naturally occurring flavonoid found in fruits and vegetables, has shown promise as a multi-target anticancer compound, but its mechanisms of action remain incompletely understood. In this study, we explored how kaempferol regulates tumor growth, immune checkpoint activity, and inflammatory mediators in two genetically distinct TNBC cell lines, MDA-MB-231 (Caucasian) and MDA-MB-468 (African American). The results showed that kaempferol significantly reduced cell viability and proliferation, induced apoptosis, and caused S-phase cell cycle arrest by inhibiting the expression of CDK1, CDK4, CDK6, and CDK7. Under cytokine stimulation, kaempferol downregulated IFN-gamma-induced PD-L1 via inhibition of the JAK1/STAT3 pathway and reduced TNF-alpha-induced CCL2 expression, indicating broad immunomodulatory activity. To understand the contribution of redox regulation, we silenced the transcription factor Nrf2 (NFE2L2) using Nrf2 siRNA. Interestingly, Nrf2 knockdown did not alter kaempferol's inhibition of PD-L1, suggesting that PD-L1 modulation occurs independently of Nrf2. In contrast, silencing Nrf2 markedly increased CCL2 and transglutaminase-2 (TGM2) expression, confirming Nrf2's repressive role in inflammatory signaling. Kaempferol treatment reversed these increases, bringing CCL2 and TGM2 levels back towards baseline. Together, these findings highlight kaempferol's dual ability to regulate both immune checkpoints and inflammatory mediators through distinct, Nrf2-dependent and independent pathways. In conclusion, this study describes the anticancer effects of kaempferol through various molecular mechanisms and targets, which may lead to the development of more effective adjuvant therapies against TNBC.
利益披露 Disclosure
S. Kaur, None..
P. Mendonca, None..
S. D. Mishra, None..
K. F. Soliman, None.