Inhibition of Wnt signaling by Frizzled7 antibody-coated nanoshells sensitizes triple-negative breast cancer cells to the autophagy regulator chloroquine.
Inhibition of Wnt signaling by Frizzled7 antibody-coated nanoshells sensitizes triple-negative breast cancer cells to the autophagy regulator chloroquine.
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Frizzled7抗体包被的纳米壳对Wnt信号的抑制使三阴性乳腺癌细胞对自噬调节剂氯喹敏感。
DOI：
10.1007/s12274-020-2795-8
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发表时间：
2020-06
期刊：
影响因子：
9.9
通讯作者：
Day ES
中科院分区：
文献类型：
--
作者：
Wang J;Dang MN;Day ES
尽管我们对三阴性乳腺癌（TNBC）背后的生物学理解有所提高，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信号是一种很有前途的对抗TNBC的策略，因为Wnt信号驱动TNBC的进展、化疗耐药和干性。然而，Wnt抑制可导致自噬上调，从而产生治疗抗性。这为联合治疗提供了机会，因为自噬抑制剂与Wnt抑制剂同时应用可以提高治疗效果。本研究将自噬抑制剂氯喹（CQ）与Frizzled7抗体包被纳米壳（FZD7- ns）联合应用于TNBC细胞，通过阻断Wnt配体/FZD7受体的相互作用来抑制Wnt信号，并在体外评估这种双重处理。我们发现FZD7-NS可以抑制典型Wnt信号的两个靶点Axin2和CyclinD1，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细胞中几个干细胞基因的表达，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联合治疗比单独治疗或CQ与游离FZD7抗体联合治疗更有效。这表明纳米载体的设计对其治疗效用很重要。总之，这些发现表明FZD7-NS和CQ联合调控Wnt信号和自噬是一种很有希望的对抗TNBC的策略。
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 in vitro. 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.
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影响因子：
5.2
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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