Targeting Cell Cycle Proteins in Breast Cancer Cells with siRNA by Using Lipid-Substituted Polyethylenimines

Authors

Manoj Parmar, University of Alberta
Hamidreza Montazeri Aliabadi, Chapman UniversityFollow
Parvin Mahdipoor, University of Alberta
Cezary Kucharski, University of Alberta
Robert Maranchuk, University of Alberta
Judith C. Hugh, University of Alberta
Hasan Uludag, University of Alberta

Document Type

Article

Publication Date

1-26-2015

Abstract

The cell cycle proteins are key regulators of cell cycle progression whose de-regulation is one of the causes of breast cancer. RNA interference (RNAi) is an endogenous mechanism to regulate gene expression and it could serve as the basis of regulating aberrant proteins including cell cycle proteins. Since the delivery of small interfering RNA (siRNA) is a main barrier for implementation of RNAi therapy, we explored the potential of a non-viral delivery system, 2.0 kDa polyethylenimines substituted with linoleic acid and caprylic acid, for this purpose. Using a library of siRNAs against cell cycle proteins, we identified cell division cycle protein 20 (CDC20), a recombinase RAD51, and serine-threonine protein kinase CHEK1 as effective targets for breast cancer therapy, and demonstrated their therapeutic potential in breast cancer MDA-MB-435, MDA-MB-231 and MCF7 cells with respect to another well-studied cell cycle protein, kinesin spindle protein. We also explored the efficacy of dicer-substrate siRNA (DsiRNA) against CDC20, RAD51 and CHEK1, where a particular DsiRNA against CDC20 showed an exceptionally high inhibition of cell growth in vitro. There was no apparent effect of silencing selected cell cycle proteins on the potency of the chemotherapy drug doxorubicin. The efficacy of DsiRNA against CDC20 was subsequently assessed in a xenograft model, which indicated a reduced tumor growth as a result of CDC20 DsiRNA therapy. The presented study highlighted specific cell cycle protein targets critical for breast cancer therapy, and provided a polymeric delivery system for their effective down-regulation.

Comments

This article was originally published in Frontiers in Bioengineering and Biotechnology, volume 3, in 2015, and has accompanying data. DOI: 10.3389/fbioe.2015.00014

Recommended Citation

Parmar M, Aliabadi HM, Mahdipoor P, Kucharski C, Maranchuk R, Hugh JC and Uludag H(2015) Targeting cell cycle proteins in breast cancer cells with siRNA by using lipid-substituted polyethylenimines. Front. Bioeng. Biotechnol 3:14. doi:10.3389/fbioe.2015.00014

Copyright

The authors

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This work is licensed under a Creative Commons Attribution 4.0 License.