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bioRxiv · 10.1101/656199

EpCAM Aptamer siRNA chimeras: Therapeutic efficacy in epithelial cancer cells.

Elchuri, S. V.·Balasubramanyam, J.·Badrinarayanan, L.·Dhaka, B.·Gowda, H.·Pandey, A.·Subramanian, K.·Lakshmi, B. S.
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Abstract

In the era of personalized medicine as well as precision medicine, targeted therapy has become an integral part of cancer treatment in conjunction with conventional chemo- and radiotherapy. We designed aptamer-siRNA chimeras that can specifically target cancers expressing EpCAM, a stem cell marker and deliver the specific siRNA required for therapy response. The siRNAs were chosen against PLK1, BCL2 and STAT3 as these oncogenes play prominent role in tumour progression of several cancers. Targeted delivery of EpCAM-siRNA chimeras resulted in cell death in several cancer cell lines such as cancers of the breast, lung, head and neck, liver and retinoblastoma. In vivo analysis of EpCAM-siRNA chimera mediated silencing on RB xenografts tumour model showed increased tumor reduction in all the three EpCAM-siRNA treated conditions. However, regulation of PLK1 exhibited higher efficacy in tumour reduction. Therefore. We studied signaling mechanism using global phosphoproteomics analysis. An increased P53 mediated downstream signalling pathway might have enabled increased apoptosis in the cancer cells. In conclusion, this study demonstrated the efficacy of EpCAM aptamer chimeras coupled to siRNA gene silencing for targeted anti-cancer therapy.\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC=\"FIGDIR/small/656199v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (48K):\norg.highwire.dtl.DTLVardef@1ce89daorg.highwire.dtl.DTLVardef@bc5daeorg.highwire.dtl.DTLVardef@aa4ceforg.highwire.dtl.DTLVardef@a1159e_HPS_FORMAT_FIGEXP M_FIG C_FIG Illustration showing how EpCAM aptamer-mediated silencing of PLK1 could control the cell cycle progression at multiple number of check points and induce apoptosis involving hyper and hypophosphorylation of variety of signalling molecules

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Elchuri, S. V., Balasubramanyam, J., Badrinarayanan, L., Dhaka, B., Gowda, H., Pandey, A., Subramanian, K., Lakshmi, B. S.. 2019-06-06. EpCAM Aptamer siRNA chimeras: Therapeutic efficacy in epithelial cancer cells.. https://doi.org/10.1101/656199

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