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Published on: March 3, 2023
The therapeutic effect of DX2 inhibition in nicotine-induced lung cancer progression
Soyoung Park1, Ah-Young Oh1, Byung-Su Hong1
1Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Republic of Korea.
Abstract:
Alternative splicing products of AIMP2 and AIMP2-DX2 (DX2) have been reported to be associated with human lung cancer. In fact, DX2 expression is elevated in human lung cancers, and DX2 transgenic mice also develop lung cancer, in particular small cell lung cancer (SCLC). However, the mechanism by which DX2 is induced during cancer progression has not been clearly elucidated. Here, we show that DX2 is induced by nicotine, the main component of smoking-related chemicals, which can stabilize the human epidermal growth factor receptor 2 (HER2) protein and transcriptionally increase sonic hedgehog (Shh). Indeed, nicotine showed tumorigenicity via DX2 by promoting spheroid formation and in vivo lung and kidney cancer progression. Moreover, the elimination of DX2 using small interfering RNA (siRNA) or an optimized inhibitor (SNU-14) blocked the induction of HER2 and Shh and completely suppressed tumor sphere formation in response to nicotine. These results indicate that DX2 is critical for lung cancer progression, and a specific DX2 inhibitor would be useful for the treatment of human cancers, including SCLC and non-SCLC (NSCLC).
Insights
Nicotine induces AIMP2-DX2 (DX2) expression, promoting lung cancer by stabilizing HER2 and increasing Shh. DX2 inhibition blocks these effects, suggesting DX2 inhibitors for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
Background:
- Alternative splicing of AIMP2 produces AIMP2-DX2 (DX2), linked to human lung cancer.
- DX2 expression is elevated in lung cancers, and its transgenic expression induces lung cancer, particularly small cell lung cancer (SCLC).
Purpose of the Study:
- To elucidate the mechanism by which DX2 is induced during cancer progression.
- To investigate the role of nicotine in DX2 induction and subsequent cancer development.
Main Methods:
- Investigated the effect of nicotine on DX2 expression and its downstream targets HER2 and Shh.
- Utilized small interfering RNA (siRNA) and a specific inhibitor (SNU-14) to block DX2.
- Assessed tumor spheroid formation and in vivo tumor progression in response to nicotine and DX2 inhibition.
Main Results:
- Nicotine induces DX2, which stabilizes HER2 and transcriptionally increases Shh.
- Nicotine promotes tumorigenicity via DX2, enhancing spheroid formation and in vivo lung and kidney cancer progression.
- DX2 elimination via siRNA or SNU-14 inhibited HER2 and Shh induction and suppressed nicotine-induced tumor sphere formation.
Conclusions:
- DX2 is critical for lung cancer progression, acting as a mediator of nicotine's tumorigenic effects.
- Targeting DX2 with specific inhibitors presents a potential therapeutic strategy for SCLC and non-SCLC (NSCLC).
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