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Targeting the interaction of AIMP2-DX2 with HSP70 suppresses cancer development

Semi Lim1, Hye Young Cho2, Dae Gyu Kim1

  • 1Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.

Nature Chemical Biology
|December 4, 2019
PubMed

Insights

Heat-shock protein HSP70 stabilizes the cancer-promoting factor AIMP2-DX2 by preventing its degradation. This interaction enhances tumor progression, offering a potential therapeutic target for cancer treatment.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • AIMP2 lacking exon 2 (AIMP2-DX2) is a tumorigenic factor frequently upregulated in various cancers.
  • The precise mechanisms regulating AIMP2-DX2 cellular levels remain largely unknown.

Purpose of the Study:

  • To identify factors determining AIMP2-DX2 cellular levels.
  • To elucidate the functional and structural basis of the interaction between AIMP2-DX2 and its regulatory factors.
  • To explore the therapeutic potential of targeting this interaction in cancer.

Main Methods:

  • Interactome analysis to identify binding partners of AIMP2-DX2.
  • X-ray crystallography and NMR spectroscopy for structural determination of the AIMP2-DX2-HSP70 complex.
  • In vitro and in vivo assays to assess the impact of the interaction on cancer progression.
  • Analysis of patient tissues for correlation between HSP70 and AIMP2-DX2 levels.

Main Results:

  • Heat-shock protein HSP70 was identified as a critical determinant of AIMP2-DX2 levels.
  • HSP70 binds to AIMP2-DX2, inhibiting its Siah1-dependent ubiquitination and degradation.
  • The AIMP2-DX2-HSP70 interaction enhances AIMP2-DX2-induced cell transformation and cancer progression in vivo.
  • A positive correlation between HSP70 and AIMP2-DX2 levels was observed in lung cancer cell lines and patient samples.
  • Chemical inhibition of the AIMP2-DX2-HSP70 interaction suppressed cancer cell growth.

Conclusions:

  • HSP70 plays a crucial role in stabilizing AIMP2-DX2, thereby promoting tumor progression.
  • The AIMP2-DX2-HSP70 interaction represents a promising therapeutic target for cancer treatment.
  • Targeting this interaction could offer a novel strategy for suppressing cancer growth.

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