Theranostics 2015; 5(12):1456-1472. doi:10.7150/thno.11692
EpCAM Aptamer-mediated Survivin Silencing Sensitized Cancer Stem Cells to Doxorubicin in a Breast Cancer Model
1. School of Nursing, Zhengzhou University, Zhengzhou, P. R. China, 450001.
2. School of Medicine, Deakin University, 75 Pigdons Road, Waurn Ponds, Victoria, 3217, Australia.
3. Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia
4. Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia
5. CSIRO Australian Animal Health Laboratory, Private Bag 24, Geelong, Victoria 3220, Australia
6. Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA.
7. Department of Gynecologic Oncology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China.
8. School of Medical Science & Griffith Health Institute, Gold Coast Campus, Griffith University, Southport, QLD 4222, Australia.
9. Institute for Frontier Materials, Deakin University, Waurn Ponds, Victoria, 3216, Australia
10. Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, P. R. China, 610041.
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.
Keywords: Breast cancer, RNA interference, Cancer stem cell, Aptamer, Survivin
Wang T, Gantier MP, Xiang D, Bean AG, Bruce M, Zhou SF, Khasraw M, Ward A, Wang L, Wei MQ, AlShamaileh H, Chen L, She X, Lin J, Kong L, Shigdar S, Duan W. EpCAM Aptamer-mediated Survivin Silencing Sensitized Cancer Stem Cells to Doxorubicin in a Breast Cancer Model. Theranostics 2015; 5(12):1456-1472. doi:10.7150/thno.11692. Available from http://www.thno.org/v05p1456.htm