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Published on: March 17, 2018
Spinosad blocks CHRNA5 mediated EGFR signaling pathway activation to inhibit lung adenocarcinoma proliferation
Hongling Zou1, Yan Chen2, Xinping Zhu3
1College of Life Science, Sichuan Normal University, Chengdu, Sichuan 610101, China; Cancer Institute of Integrative Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang 310012, China.
Abstract:
Lung adenocarcinoma (LUAD) is the leading cause of cancer death worldwide, with high incidence and low survival rates. Nicotinic acetylcholine receptors play an important role in the progression of LUAD. In this study, a screening of 17 nicotinic acetylcholine receptor allosteric agents revealed that spinosad effectively suppressed the proliferation of LUAD cells. The experiments demonstrated that spinosad induced cell cycle arrest in the G1 phase and stimulated apoptosis, thereby impeding the growth of LUAD and enhancing the responsiveness to gefitinib in vitro and vivo. Mechanistic insights obtained through transcriptome sequencing, Co-IP, and protein immunoblots indicated that spinosad disrupted the interaction between CHRNA5 and EGFR, thereby inhibiting the formation of downstream complexes and activation of the EGFR signaling pathway. The supplementation of exogenous acetylcholine showed to mitigate the inhibition of LUAD cell proliferation induced by spinosad. This study elucidates the therapeutic effects and mechanisms of spinosad in LUAD, and offers a theoretical and experimental foundation for novel LUAD treatments.
Insights
Spinosad, a nicotinic acetylcholine receptor agent, inhibits lung adenocarcinoma (LUAD) growth by inducing cell cycle arrest and apoptosis. It also enhances gefitinib response by disrupting CHRNA5-EGFR interactions.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Lung adenocarcinoma (LUAD) presents a significant global health challenge due to high mortality and low survival rates.
- Nicotinic acetylcholine receptors are implicated in LUAD progression, suggesting them as potential therapeutic targets.
Purpose of the Study:
- To investigate the efficacy of spinosad, a nicotinic acetylcholine receptor allosteric agent, in suppressing LUAD cell proliferation.
- To elucidate the underlying mechanisms by which spinosad affects LUAD growth and its interaction with gefitinib.
Main Methods:
- Screening of 17 nicotinic acetylcholine receptor allosteric agents.
- In vitro and in vivo experiments assessing cell cycle arrest, apoptosis, and gefitinib responsiveness.
- Transcriptome sequencing, Co-immunoprecipitation (Co-IP), and protein immunoblotting to determine molecular mechanisms.
Main Results:
- Spinosad demonstrated significant suppression of LUAD cell proliferation.
- Spinosad induced G1 phase cell cycle arrest and stimulated apoptosis in LUAD cells.
- Spinosad disrupted the CHRNA5-EGFR interaction, inhibiting EGFR signaling pathway activation and enhancing gefitinib efficacy.
- Exogenous acetylcholine partially reversed spinosad's inhibitory effects on LUAD cell proliferation.
Conclusions:
- Spinosad exhibits therapeutic potential for LUAD by inhibiting proliferation and enhancing gefitinib sensitivity.
- The mechanism involves the disruption of CHRNA5-EGFR interaction and subsequent EGFR pathway inhibition.
- This study provides a foundation for developing novel spinosad-based treatments for lung adenocarcinoma.
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