Chemical suppression of an oncogenic splicing variant of AIMP2 induces tumour regression

AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein 2) is a potent tumour suppressor that induces apoptosis in response to various oncogenic signals. AIMP2-DX2, an exon2-deleted splicing variant of AIMP2, is up-regulated in lung cancer and competitively suppresses the pro-apoptotic...

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Veröffentlicht in:Biochemical journal 2013-09, Vol.454 (3), p.411-416
Hauptverfasser: Lee, Hee Sook, Kim, Dae Gyu, Oh, Young Sun, Kwon, Nam Hoon, Lee, Jin Young, Kim, Doyeun, Park, Song-Hwa, Song, Jong-Hwan, Lee, Sunkyung, Han, Jung Min, Park, Bum-Joon, Lee, Jongkook, Kim, Sunghoon
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Sprache:eng
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Zusammenfassung:AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein 2) is a potent tumour suppressor that induces apoptosis in response to various oncogenic signals. AIMP2-DX2, an exon2-deleted splicing variant of AIMP2, is up-regulated in lung cancer and competitively suppresses the pro-apoptotic activity of AIMP2, resulting in tumorigenesis. In the present study we report that BC-DXI01, a synthetic compound, specifically reduces the cellular levels of AIMP2-DX2 through selective degradation of the AIMP2-DX2 mRNA transcript. We found that BC-DXI01-mediated cell death positively correlates with AIMP2-DX2 expression in the lung cancer cell lines tested. Administration of BC-DXI01 in a AIMP2-DX2-driven tumour xenograft mice model led to reduced tumour sizes and volumes of up to 60% in comparison with vehicle-treated mice group, consistent with decreases in AIMP2-DX2 transcript and protein levels. Taken together, our findings suggest that tumorigenic activity of AIMP2-DX2 can be controlled by the small chemical BC-DXI01, which can selectively suppress the AIMP2-DX2 mRNA transcript.
ISSN:0264-6021
1470-8728
DOI:10.1042/BJ20130550