Wang Jianxin, Dang Megan N, Day Emily S
Department of Biomedical Engineering, University of Delaware, Newark, DE 19716, USA.
Department of Materials Science and Engineering, University of Delaware, Newark, DE 19716, USA.
Nano Res. 2020 Jun;13(6):1693-1703. doi: 10.1007/s12274-020-2795-8. Epub 2020 Apr 25.
Despite improvements in our understanding of the biology behind triple-negative breast cancer (TNBC), it remains a devastating disease due to lack of an effective targeted therapy. Inhibiting Wnt signaling is a promising strategy to combat TNBC because Wnt signaling drives TNBC progression, chemoresistance, and stemness. However, Wnt inhibition can lead to upregulation of autophagy, which confers therapeutic resistance. This provides an opportunity for combination therapy, as autophagy inhibitors applied concurrently with Wnt inhibitors could increase treatment efficacy. Here, we applied the autophagy inhibitor chloroquine (CQ) to TNBC cells in combination with Frizzled7 antibody-coated nanoshells (FZD7-NS) that suppress Wnt signaling by blocking Wnt ligand/FZD7 receptor interactions, and evaluated this dual treatment . We found that FZD7-NS can inhibit Axin2 and CyclinD1, two targets of canonical Wnt signaling, and increase the expression of LC3, an autophagy marker. When FZD7-NS and CQ are applied together, they reduce the expression of several stemness genes in TNBC cells, leading to inhibition of TNBC cell migration and self-renewal. Notably, co-delivery of FZD7-NS and CQ is more effective than either therapy alone or the combination of CQ with free FZD7 antibodies. This demonstrates that the nanocarrier design is important to its therapeutic utility. Overall, these findings indicate that combined regulation of Wnt signaling and autophagy by FZD7-NS and CQ is a promising strategy to combat TNBC.
尽管我们对三阴性乳腺癌（TNBC）背后的生物学机制的理解有所进步，但由于缺乏有效的靶向治疗，它仍然是一种毁灭性的疾病。抑制Wnt信号通路是对抗TNBC的一种有前景的策略，因为Wnt信号通路驱动TNBC的进展、化疗耐药性和干性。然而，Wnt抑制可导致自噬上调，从而赋予治疗抗性。这为联合治疗提供了机会，因为自噬抑制剂与Wnt抑制剂同时应用可提高治疗效果。在这里，我们将自噬抑制剂氯喹（CQ）与通过阻断Wnt配体/FZD7受体相互作用来抑制Wnt信号通路的卷曲蛋白7抗体包被的纳米壳（FZD7-NS）联合应用于TNBC细胞，并评估了这种双重治疗。我们发现FZD7-NS可以抑制经典Wnt信号通路的两个靶点Axin2和细胞周期蛋白D1，并增加自噬标志物LC3的表达。当FZD7-NS和CQ一起应用时，它们会降低TNBC细胞中几种干性基因的表达，从而抑制TNBC细胞的迁移和自我更新。值得注意的是，FZD7-NS和CQ的共同递送比单独使用任何一种疗法或CQ与游离FZD7抗体的组合更有效。这表明纳米载体设计对其治疗效用很重要。总体而言，这些发现表明，FZD7-NS和CQ联合调节Wnt信号通路和自噬是对抗TNBC的一种有前景的策略。
