TY - JOUR
T1 - Modulation of MKNK2 alternative splicing by splice-switching oligonucleotides as a novel approach for glioblastoma treatment
AU - Mogilevsky, Maxim
AU - Shimshon, Odelia
AU - Kumar, Saran
AU - Mogilevsky, Adi
AU - Keshet, Eli
AU - Yavin, Eylon
AU - Heyd, Florian
AU - Karni, Rotem
N1 - Publisher Copyright:
© The Author(s) 2018.
PY - 2018/11/30
Y1 - 2018/11/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85061126524&partnerID=8YFLogxK
U2 - 10.1093/nar/gky921
DO - 10.1093/nar/gky921
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C2 - 30329087
AN - SCOPUS:85061126524
SN - 0305-1048
VL - 46
SP - 11396
EP - 11404
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 21
ER -