Single and Combinational siRNA Therapy of Cancer Cells: Probing Changes in Targeted and Nontargeted Mediators after siRNA Treatment.
Cancer cells are known to be heterogeneous and plastic, which imparts innate and acquired abilities to resist molecular targeting by short interfering RNA (siRNA). Not all cancer cells in a population would show a similar responsiveness to targeting of genes critical for their survival and even the responders could quickly transform and switch to alternative mechanism(s) for their survival. This study was designed to look at this phenomenon by analyzing the effect of siRNA silencing of selected protein mRNAs involved in cell survival and proliferation on other protein mRNAs that could contribute to cell survival. We compared the gene expression profile of the initial population after siRNA silencing to the subpopulation that survived the siRNA silencing, to identify potential overexpressions that might explain the cell survival. Our studies show that silencing well-selected protein mRNAs simultaneously could offer advantages compared to individual siRNA silencing due to an additional impact on the expression level of certain protein mRNAs. We also demonstrate that overexpression of certain protein mRNAs could explain the innate unresponsiveness of a subpopulation of cells. These observations could be a stepping stone for further investigation of the possibility of significant synergistic effect for this combinational RNA interference strategy.
Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University , Irvine, California 92618, United States.|Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta , Edmonton, AB T6G 2G6, Canada.
Hamidreza Montazeri
HM
Aliabadi
Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta , Edmonton, AB T6G 2G6, Canada.
Parvin
P
Mahdipoor
Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University , Irvine, California 92618, United States.|Schmid College of Science and Technology; Biological Sciences, Chapman University , Orange, California 92866, United States.
Marco
M
Bisoffi
Department of Pathology & Laboratory Medicine, Faculty of Medicine & Dentistry, University of Alberta , Edmonton, AB T6G 2B7, Canada.
Judith C
JC
Hugh
Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta , Edmonton, AB T6G 2G6, Canada.|Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta , Edmonton, AB T6G 2E1, Canada.|Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta , Edmonton, AB T6G 2R3, Canada.
Hasan
H
Uludağ
D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D059467:Transcriptome; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; D004317:Doxorubicin
cancer cells; pathways; signaling; silencing; small interfering RNA (siRNA)