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Inhibiting DX2-p14/ARF Interaction Exerts Antitumor Effects in Lung Cancer and Delays Tumor Progression
Ah-Young Oh1, Youn Sang Jung1, Jiseon Kim2
1Department of Molecular Biology, Pusan National University, Busan, Republic of Korea (South).
Abstract:
The aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) splice variant designated DX2 is induced by cigarette smoke carcinogens and is often detected in human lung cancer specimens. However, the function of DX2 in lung carcinogenesis is obscure. In this study, we found that DX2 expression was induced by oncogenes in human lung cancer tissues and cells. DX2 prevented oncogene-induced apoptosis and senescence and promoted drug resistance by directly binding to and inhibiting p14/ARF. Through chemical screening, we identified SLCB050, a novel compound that blocks the interaction between DX2 and p14/ARF in vitro and in vivo SLCB050 reduced the viability of human lung cancer cells, especially small cell lung cancer cells, in a p14/ARF-dependent manner. Moreover, in a mouse model of K-Ras-driven lung tumorigenesis, ectopic expression of DX2 induced small cell and non-small cell lung cancers, both of which could be suppressed by SLCB050 treatment. Taken together, our findings show how DX2 promotes lung cancer progression and how its activity may be thwarted as a strategy to treat patients with lung cancers exhibiting elevated DX2 levels. Cancer Res; 76(16); 4791-804. ©2016 AACR.
Insights
A lung cancer splice variant, DX2, promotes tumor growth by inhibiting p14/ARF. A new compound, SLCB050, blocks this interaction, reducing cancer cell viability and suppressing tumor development in mice.
Area of Science:
- Oncology
- Molecular Biology
- Carcinogenesis
Background:
- The AIMP2 splice variant DX2 is linked to lung cancer and induced by carcinogens.
- The precise role of DX2 in lung carcinogenesis remains unclear.
Purpose of the Study:
- To elucidate the function of DX2 in lung cancer progression.
- To identify therapeutic strategies targeting DX2 in lung cancer.
Main Methods:
- Investigated DX2 expression in human lung cancer tissues and cells.
- Assessed DX2's interaction with p14/ARF and its impact on apoptosis and senescence.
- Screened for compounds inhibiting the DX2-p14/ARF interaction.
- Evaluated the efficacy of a novel compound (SLCB050) in vitro and in vivo mouse models.
Main Results:
- DX2 expression is induced by oncogenes and promotes lung cancer by inhibiting p14/ARF, preventing apoptosis and senescence, and enhancing drug resistance.
- SLCB050 effectively blocks DX2-p14/ARF interaction, reducing lung cancer cell viability, particularly in small cell lung cancer.
- SLCB050 treatment suppressed both small cell and non-small cell lung cancers in a K-Ras-driven mouse model.
Conclusions:
- DX2 is a key driver of lung cancer progression by interfering with p14/ARF.
- Targeting the DX2-p14/ARF interaction with compounds like SLCB050 presents a promising therapeutic strategy for lung cancer patients with elevated DX2 levels.
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