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.
摘要：
肺腺癌（LUAD）是全球癌症死亡的主要原因，发病率高，生存率低。烟碱乙酰胆碱受体在LUAD的进展中起重要作用。在这项研究中,对17种烟碱乙酰胆碱受体变构剂的筛选显示，多杀菌素有效抑制了LUAD细胞的增殖。实验证明,多杀菌素诱导细胞周期阻滞在G1期,并刺激细胞凋亡,从而阻碍LUAD的生长，并在体外和体内增强对吉非替尼的反应性。通过转录组测序获得的机制见解，共同IP,和蛋白质免疫印迹表明多杀菌素破坏了CHRNA5和EGFR之间的相互作用，从而抑制下游复合物的形成和EGFR信号通路的激活。补充外源性乙酰胆碱可以减轻多杀菌素对LUAD细胞增殖的抑制作用。本研究阐明了多杀菌素在LUAD中的治疗作用和机制。为新型LUAD治疗提供了理论和实验基础。
