7965

AIMP2

JTV-1|JTV1|P38|PRO0992;aminoacyl tRNA synthetase complex-interacting multifunctional protein 2;AIMP2;aminoacyl tRNA synthetase complex-interacting multifunctional protein 2

ARS-interacting multi-functional protein 2|aminoacyl tRNA synthase complex-interacting multifunctional protein 2|multisynthase complex auxiliary component p38|multisynthetase complex auxiliary component p38|protein JTV-1

7p22

protein-coding

Aminoacyl-transfer ribonucleic acid (tRNA) synthetases-interacting multifunctional protein (AIMP) 2 is a factor associated with the macromolecular protein synthesis machinery consisting of nine different aminoacyl-tRNA synthetases and three non-enzymatic factors. However, it was shown to work as a multifaceted regulator through the versatile interactions with diverse signal mediators. For instance, it can mediate pro-apoptotic response to DNA damage and tumor necrosis factor-alpha (TNF-alpha) stimulus and growth-arresting signal by transforming growth factor (TGF)-beta. Considering that these pathways are critically implicated in the control of tumorigenesis, AIMP2 is expected to work as a potent tumor suppressor with broad coverage against different cancer types. Here we investigated whether AIMP2 would give gene dosage effect on its pro-apoptotic and anti-proliferative activities using the wild-type, hetero- and homozygous AIMP2 cells and whether AIMP2 would be critical in preventing tumorigenesis using different in vivo tumor models. Both the apoptotic responses to DNA damage and TNF-alpha and sensitivity to growth arresting TGF-beta signal were reduced in AIMP2 hetero- and homozygous cells compared with the wild-type cells in dose-dependent manner. In all the in vivo carcinogenesis experiments, reduction of AIMP2 level in heterozygous AIMP2 mice provided higher susceptibility to tumor formation. Thus, this work proves the functional significance of AIMP2 in determination of cell proliferation and death, and as a haploinsufficient tumor suppressor.

Chemoresistance is a main cause for the failure of cancer management and intensive investigation is on-going to control chemoresistant (CR) cancers. Although NF-kappaB has been suggested as one of the potential targets to alleviate chemoresistance of epithelial ovarian cancer (EOC), direct targeting of NF-kappaB may result in an unexpected effect due to the complex regulatory network via NF-kappaB. Here we show that AIMP2-DX2, a splicing variant of tumor suppressor AIMP2, can be a therapeutic target to control CR EOC. AIMP2-DX2 was often highly expressed in CR EOC both in vitro and in vivo. AIMP2-DX2 compromised the tumor necrosis factor alpha-dependent pro-apoptotic activity of AIMP2 via the competitive inhibition of AIMP2 binding to TRAF2 that plays a pivotal role in the regulation of NF-kappaB. The direct delivery of siRNA against AIMP2-DX2 into abdominal metastatic tumors of ovarian cancer using a microneedle converged on microendoscopy significantly suppressed the growth rate of tumors. The treated cancer tissues showed an enhanced apoptosis and the decreased TRAF2 level. Thus, we suggest that the downregulation of AIMP2-DX2 can be a potent adjuvant therapeutic approach for CR EOC that resulted from an aberrant activity of NF-kappaB.