Ghasri Amirhesam, Bahri Hampa Sepideh, Mirzaee Godarzee Mohadeseh, Babashah Sadegh, Sadeghizadeh Majid
Department of Molecular Genetics, Faculty of Biological Sciences, Trabiat Modares University, Tehran, Iran.
Med Oncol. 2025 Jul 28;42(9):381. doi: 10.1007/s12032-025-02960-6.
Breast cancer ranks as one of the most prevalent cancers impacting women worldwide, posing significant treatment challenges due to chemotherapy resistance and high recurrence rates. This study investigates the therapeutic potential of Dendrosomal Nanocurcumin (DNC), a novel formulation aimed at enhancing curcumin's bioavailability. The focus is on its impact on the Wnt/β-catenin signaling pathway via the modulation of the PIWIL2 protein in MCF-7 breast cancer cells.The Wnt/β-catenin signaling pathway is crucial for controlling cell proliferation, differentiation, and apoptosis. Its dysregulation is strongly linked to breast cancer progression. PIWIL2, a member of the PIWI subfamily of Argonaute proteins, plays a role in RNA silencing, DNA methylation, histone modification, gene transcription regulation, and interactions with oncogenic pathways. These functions highlight its importance in gene regulation, stem cell maintenance, and cancer progression.In this study, MCF-7 cells were treated with Dendrosomal Nanocurcumin at a dose of 20µM for 48 h, based on the IC50 determined from the MTT assay. Real-time PCR analysis revealed that DNC treatment significantly reduced the expression levels of β-catenin (p < 0.0001), Cyclin D1 (p < 0.0001), and PIWIL2 (p < 0.00001), while significantly increasing the expression of GSK3β (p < 0.0001).These findings were supported by Western blot analysis, which showed a significant decline in both phosphorylated and non-phosphorylated forms of β-catenin and PIWIL2 proteins. This suggests that DNC disrupts the Wnt/β-catenin signaling pathway by reducing the stability and cytoplasmic accumulation of β-catenin. The reduction in β-catenin likely prevents its nuclear translocation and the subsequent activation of target genes like Cyclin D1, thus inhibiting cell proliferation and promoting apoptosis. Furthermore, a significant decrease in PIWIL2 protein levels in DNC-treated cells indicates that DNC targets PIWIL2, further inhibiting the Wnt/β-catenin signaling pathway and reducing the oncogenic potential of MCF-7 breast cancer cells.These findings highlight the potential of DNC as an effective treatment option for breast cancer, particularly in overcoming resistance to conventional therapies. Further research is necessary to gain a comprehensive understanding the mechanisms of DNC and its clinical efficacy, offering hope for enhanced breast cancer treatment strategies.
乳腺癌是全球影响女性的最常见癌症之一，由于化疗耐药性和高复发率，带来了重大的治疗挑战。本研究调查了树枝状纳米姜黄素（DNC）的治疗潜力，这是一种旨在提高姜黄素生物利用度的新型制剂。重点是其通过调节MCF-7乳腺癌细胞中的PIWIL2蛋白对Wnt/β-连环蛋白信号通路的影响。Wnt/β-连环蛋白信号通路对于控制细胞增殖、分化和凋亡至关重要。其失调与乳腺癌进展密切相关。PIWIL2是Argonaute蛋白PIWI亚家族的成员，在RNA沉默、DNA甲基化、组蛋白修饰、基因转录调控以及与致癌途径的相互作用中发挥作用。这些功能突出了其在基因调控、干细胞维持和癌症进展中的重要性。在本研究中，根据MTT试验确定的IC50，用20µM剂量的树枝状纳米姜黄素处理MCF-7细胞48小时。实时PCR分析显示，DNC处理显著降低了β-连环蛋白（p < 0.0001）、细胞周期蛋白D1（p < 0.0001）和PIWIL2（p < 0.00001）的表达水平，同时显著增加了GSK3β的表达（p < 0.0001）。蛋白质印迹分析支持了这些发现，该分析显示β-连环蛋白和PIWIL2蛋白的磷酸化和非磷酸化形式均显著下降。这表明DNC通过降低β-连环蛋白的稳定性和细胞质积累来破坏Wnt/β-连环蛋白信号通路。β-连环蛋白的减少可能会阻止其核转位以及随后对细胞周期蛋白D1等靶基因的激活，从而抑制细胞增殖并促进凋亡。此外，DNC处理的细胞中PIWIL2蛋白水平显著降低表明DNC靶向PIWIL2，进一步抑制Wnt/β-连环蛋白信号通路并降低MCF-7乳腺癌细胞的致癌潜力。这些发现突出了DNC作为乳腺癌有效治疗选择的潜力，特别是在克服对传统疗法的耐药性方面。有必要进行进一步的研究以全面了解DNC的作用机制及其临床疗效，为增强乳腺癌治疗策略带来希望。
