Modulation of MKNK2 alternative splicing by splice-switching oligonucleotides as a novel approach for glioblastoma treatment

Maxim Mogilevsky, Odelia Shimshon, Saran Kumar, Adi Mogilevsky, Eli Keshet, Eylon Yavin, Florian Heyd, Rotem Karni*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

The gene encoding the kinase Mnk2 (MKNK2) is alternatively spliced to produce two isoforms––Mnk2a and Mnk2b. We previously showed that Mnk2a is downregulated in several types of cancer and acts as a tumor suppressor by activation of the p38–MAPK stress pathway, inducing apoptosis. Moreover, Mnk2a overexpression suppressed Ras-induced transformation in culture and in vivo. In contrast, the Mnk2b isoform acts as a pro-oncogenic factor. In this study, we designed modified-RNA antisense oligonucleotides and screened for those that specifically induce a strong switch in alternative splicing of the MKNK2 gene (splice switching oligonucleotides or SSOs), elevating the tumor suppressive isoform Mnk2a at the expense of the pro-oncogenic isoform Mnk2b. Induction of Mnk2a by SSOs in glioblastoma cells activated the p38–MAPK pathway, inhibited the oncogenic properties of the cells, re-sensitized the cells to chemotherapy and inhibited glioblastoma development in vivo. Moreover, inhibition of p38–MAPK partially rescued glioblastoma cells suggesting that most of the anti-oncogenic activity of the SSO is mediated by activation of this pathway. These results suggest that manipulation of MKNK2 alternative splicing by SSOs is a novel approach to inhibit glioblastoma tumorigenesis.

Original languageAmerican English
Pages (from-to)11396-11404
Number of pages9
JournalNucleic Acids Research
Volume46
Issue number21
DOIs
StatePublished - 30 Nov 2018

Bibliographical note

Funding Information:
Israel Science Foundation (ISF) [1290/12 to R.K.]; Germany–Israel Science Foundation (GIF) [I-335-207.3-2014 to R.K., F.H.]. Israel Innovation Authority [Kamin grant 63369 to R.K.]. Funding for open access charge: Grants of corresponding author. Conflict of interest statement. None declared.

Funding Information:
The authors wish to thank Dr Zahava Siegfried for comments on the manuscript, Dr Ronit Sachi–Fainero for the mCherry retroviral vector and for mCherry-labeled U87MG cells and Dr Galia Blum for help with mice imaging. Israel Science Foundation (ISF) [1290/12 to R.K.]; Germany–Israel Science Foundation (GIF) [I-335-207.3-2014 to R.K., F.H.]. Israel Innovation Authority [Kamin grant 63369 to R.K.]. Funding for open access charge: Grants of corresponding author. Conflict of interest statement. None declared.

Publisher Copyright:
© The Author(s) 2018.

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