EpCAM aptamer-mediated survivin silencing sensitized cancer stem cells to doxorubicin in a breast cancer model

Tao Wang, Michael Paul Marie Gantier, Dongxi Xiang, Andrew G Bean, Matthew P Bruce, Shu-Feng Zhou, Mustafa Khasraw, Alister C Ward, Li Wang, Ming Qian Wei, Hadi AlShamaileh, Lijue Chen, Xiaodong She, Jia Lin, Lingxue Kong, Sarah L Shigdar, Wei Duan

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Abstract

Understanding the molecular basis of drug resistance and utilising this information to overcome chemoresistance remains a key challenge in oncology. Here we report that survivin, a key protein implicated in drug resistance, is overexpressed in cancer stem cell pool of doxorubicin-resistant breast cancer cells. Moreover, by utilising an active targeting system consisting of an RNA aptamer targeted against the epithelial cell adhesion molecule and a Dicer substrate survivin siRNA, we could deliver a high dose of the siRNA to cancer stem cells in xenograft tumours. Importantly, silencing of survivin with this aptamer-siRNA chimera in cancer stem cell population led to the reversal of chemoresistance, such that combined treatment with low dose of doxorubicin inhibited stemness, eliminated cancer stem cells via apoptosis, suppressed tumour growth, and prolonged survival in mice bearing chemoresistant tumours. This strategy for in vivo cancer stem cell targeting has wide application for future effective silencing of anti-death genes and in fact any dysregulated genes involved in chemoresistance and tumour relapse.
Original languageEnglish
Pages (from-to)1456 - 1472
Number of pages17
JournalTheranostics
Volume5
Issue number12
DOIs
Publication statusPublished - 2015

Cite this

Wang, T., Gantier, M. P. M., Xiang, D., Bean, A. G., Bruce, M. P., Zhou, S-F., Khasraw, M., Ward, A. C., Wang, L., Wei, M. Q., AlShamaileh, H., Chen, L., She, X., Lin, J., Kong, L., Shigdar, S. L., & Duan, W. (2015). EpCAM aptamer-mediated survivin silencing sensitized cancer stem cells to doxorubicin in a breast cancer model. Theranostics, 5(12), 1456 - 1472. https://doi.org/10.7150/thno.11692