Targeting the interaction of AIMP2-DX2 with HSP70 suppresses cancer development.
Semi LimHye Young ChoDae Gyu KimYounah RohSe-Young SonAmeeq Ul MushtaqMinkyoung KimDeepak BhattaraiAneesh SivaramanYoungjin LeeJihye LeeWon Suk YangHoi Kyoung KimMyung Hee KimKyeong LeeYoung Ho JeonSunghoon KimPublished in: Nature chemical biology (2019)
A tumorigenic factor, AIMP2 lacking exon 2 (AIMP2-DX2), is often upregulated in many cancers. However, how its cellular level is determined is not understood. Here, we report heat-shock protein HSP70 as a critical determinant for the level of AIMP2-DX2. Interaction of the two factors was identified by interactome analysis and structurally determined by X-ray crystallography and NMR analyses. HSP70 recognizes the amino (N)-terminal flexible region, as well as the glutathione S-transferase domain of AIMP2-DX2, via its substrate-binding domain, thus blocking the Siah1-dependent ubiquitination of AIMP2-DX2. AIMP2-DX2-induced cell transformation and cancer progression in vivo was further augmented by HSP70. A positive correlation between HSP70 and AIMP2-DX2 levels was shown in various lung cancer cell lines and patient tissues. Chemical intervention in the AIMP2-DX2-HSP70 interaction suppressed cancer cell growth in vitro and in vivo. Thus, this work demonstrates the importance of the interaction between AIMP2-DX2 and HSP70 on tumor progression and its therapeutic potential against cancer.
Keyphrases
- heat shock protein
- heat shock
- papillary thyroid
- heat stress
- squamous cell
- randomized controlled trial
- gene expression
- high resolution
- lymph node metastasis
- squamous cell carcinoma
- magnetic resonance
- childhood cancer
- oxidative stress
- computed tomography
- cell therapy
- long non coding rna
- endothelial cells
- solid state
- amino acid
- cancer therapy