Oncotarget

Priority Research Papers:

Induction of DISE in ovarian cancer cells in vivo

Andrea E. Murmann, Kaylin M. McMahon, Ashley Haluck-Kangas, Nandini Ravindran, Monal Patel, Calvin Y. Law, Sonia Brockway, Jian-Jun Wei, C. Shad Thaxton, Marcus E. Peter _

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Oncotarget. 2017; 8:84643-84658. https://doi.org/10.18632/oncotarget.21471

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Abstract

Andrea E. Murmann1, Kaylin M. McMahon3,6, Ashley Haluck-Kangas1, Nandini Ravindran1, Monal Patel1, Calvin Y. Law1, Sonia Brockway1, Jian-Jun Wei4, C. Shad Thaxton3,5,6,7 and Marcus E. Peter1,2,5

1 Department of Medicine/Division of Hematology/Oncology, Feinberg School of Medicine, Chicago, IL, USA

2 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Chicago, IL, USA

3 Department of Urology, Feinberg School of Medicine, Chicago, IL, USA

4 Department of Pathology and Obstetrics and Gynecology, Feinberg School of Medicine, Chicago, IL, USA

5 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University, Chicago, IL, USA

6 Simpson Querrey Institute (SQI) for BioNanotechnology, Chicago, IL, USA

7 International Institute for Nanotechnology, Evanston, IL, USA

Correspondence to:

Marcus E. Peter, email:

Keywords: RNAi, Fas, ovarian cancer, TLP nanoparticles, cell death

Received: January 23, 2017 Accepted: September 13, 2017 Published: October 04, 2017

Abstract

The death receptor CD95/Fas can be activated by immune cells to kill cancer cells. shRNAs and siRNAs derived from CD95 or CD95 ligand (CD95L) are highly toxic to most cancer cells. We recently found that these sh/siRNAs kill cancer cells in the absence of the target by targeting the 3’UTRs of critical survival genes through canonical RNAi. We have named this unique form of off-target effect DISE (for death induced by survival gene elimination). DISE preferentially kills transformed cells and cancer stem cells. We demonstrate that DISE induction occurs in cancer cells in vivo after introducing a lentiviral CD95L derived shRNA (shL3) into HeyA8 ovarian cancer cells grown as i.p. xenografts in mice, when compared to a scrambled shRNA. To demonstrate the possibility of therapeutically inducing DISE, we coupled siRNAs to templated lipoprotein nanoparticles (TLP). In vitro, TLPs loaded with a CD95L derived siRNA (siL3) selectively silenced a biosensor comprised of Venus and CD95L ORF and killed ovarian cancer cells. In vivo, two siRNA-TLPs (siL2-TLP and siL3-TLP) reduced tumor growth similarly as observed for cells expressing the shL3 vector. These data suggest that it is possible to kill ovarian cancer cells in vivo via DISE induction using siRNA-TLPs.


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