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Nano Research 2020, 13(6): 1693-1703 https://doi.org/10.1007/s12274-020-2795-8
Research Article | Issue | Published: 25 April 2020

Inhibition of Wnt signaling by Frizzled7 antibody-coated nanoshells sensitizes triple-negative breast cancer cells to the autophagy regulator chloroquine

Show Author's Information Jianxin Wang1,  Megan N. Dang1,  Emily S. Day1,2,3( )
Department of Biomedical Engineering, University of Delaware, Newark, DE 19716, USA
Department of Materials Science and Engineering, University of Delaware, Newark, DE 19716, USA
Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA
Keywords:
nanoparticles, nanomedicine, combination therapy, antibody delivery, cancer stem cells
Topics:
Antibodies Cell death DiseasesNanoshells Nanostructured materialsSignaling
Cite this article:
Wang J, Dang MN, Day ES. Inhibition of Wnt signaling by Frizzled7 antibody-coated nanoshells sensitizes triple-negative breast cancer cells to the autophagy regulator chloroquine. Nano Research, 2020, 13(6): 1693-1703. https://doi.org/10.1007/s12274-020-2795-8
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Abstract Full text Electronic supplementary material About this article

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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Abstract
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Electronic supplementary material
About this article

Inhibition of Wnt signaling by Frizzled7 antibody-coated nanoshells sensitizes triple-negative breast cancer cells to the autophagy regulator chloroquine

Show Author's information Jianxin Wang1, Megan N. Dang1, Emily S. Day1,2,3( )
Department of Biomedical Engineering, University of Delaware, Newark, DE 19716, USA
Department of Materials Science and Engineering, University of Delaware, Newark, DE 19716, USA
Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA

Abstract

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.

Keywords: nanoparticles, nanomedicine, combination therapy, antibody delivery, cancer stem cells

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Acknowledgements

Publication history

Received: 03 March 2020
Revised: 01 April 2020
Accepted: 06 April 2020
Published: 25 April 2020
Issue date: June 2020

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© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020

Acknowledgements

This work was supported with funding from the National Institutes of Health (NIH) under grant numbers R35GM119659 and R01CA211925. The content is solely the responsibility of the authors and does not necessarily represent the views of the NIH.

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