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Abstract：
Lung cancer is a leading cause of mortality worldwide, especially among Asian patients with non-small cell lung cancer (NSCLC) who have epidermal growth factor receptor (EGFR) mutations. Initially, first-generation EGFR tyrosine kinase inhibitors (TKIs) are commonly administered as the primary treatment option; however, encountering resistance to these medications poses a significant obstacle. Hence, it has become crucial to address initial resistance and ensure continued effectiveness. Recent research has focused on the role of long noncoding RNAs (lncRNAs) in tumor drug resistance, especially lncRNA H19. β-elemene, derived from Curcuma aromatic Salisb., has shown strong anti-tumor effects. However, the relationship between β-elemene, lncRNA H19, and gefitinib resistance in NSCLC is unclear. This study aims to investigate whether β-elemene can enhance the sensitivity of gefitinib-resistant NSCLC cells to gefitinib and to elucidate its mechanism of action. The impact of gefitinib and β-elemene on cell viability was evaluated using the cell counting kit-8 (CCK8) assay. Furthermore, western blotting and qRT-PCR analysis were employed to determine the expression levels of autophagy-related proteins and genes, respectively. The influence on cellular proliferation was gauged through a colony-formation assay, and apoptosis induction was quantified via flow cytometry. Additionally, the tumorigenic potential in vivo was assessed using a xenograft model in nude mice. The expression levels of LC3B, EGFR, and Rab7 proteins were examined through immunofluorescence. Our findings elucidate that the resistance to gefitinib is intricately linked with the dysregulation of autophagy and the overexpression of lncRNA H19. The synergistic administration of β-elemene and gefitinib markedly attenuated the proliferative capacity of resistant cells, expedited apoptotic processes, and inhibited the in vivo proliferation of lung cancer. Notably, β-elemene profoundly diminished the expression of lncRNA H19 and curtailed autophagic activity in resistant cells, thereby bolstering their responsiveness to gefitinib. Moreover, β-elemene disrupted the Rab7-facilitated degradation pathway of EGFR, facilitating its repositioning to the plasma membrane. β-elemene emerges as a promising auxiliary therapeutic for circumventing gefitinib resistance in NSCLC, potentially through the regulation of lncRNA H19-mediated autophagy. The participation of Rab7 in this dynamic unveils novel insights into the resistance mechanisms operative in lung cancer, paving the way for future therapeutic innovations.
摘要：
肺癌是全球死亡的主要原因，尤其是在有表皮生长因子受体(EGFR)突变的非小细胞肺癌(NSCLC)亚洲患者中.最初，第一代EGFR酪氨酸激酶抑制剂(TKIs)通常作为主要治疗选择;然而,遇到对这些药物的耐药性是一个重大障碍。因此，解决最初的阻力并确保持续有效已变得至关重要。最近的研究集中在长链非编码RNA（lncRNAs）在肿瘤耐药中的作用，尤其是lncRNAH19.β-榄香烯,来自姜黄芳香盐。,显示出强烈的抗肿瘤作用。然而,β-榄香烯之间的关系，NSCLC中的lncRNAH19和吉非替尼耐药尚不清楚。本研究旨在探讨β-榄香烯是否能增强吉非替尼耐药NSCLC细胞对吉非替尼的敏感性，并阐明其作用机制。使用细胞计数试剂盒-8(CCK8)测定评价吉非替尼和β-榄香烯对细胞活力的影响。此外，蛋白质印迹和qRT-PCR分析用于确定自噬相关蛋白和基因的表达水平，分别。对细胞增殖的影响通过集落形成试验来衡量，凋亡诱导通过流式细胞术定量。此外,使用裸鼠异种移植模型评估体内致瘤潜能.LC3B的表达水平,EGFR,通过免疫荧光检查Rab7蛋白。我们的发现阐明了对吉非替尼的抗性与自噬的失调和lncRNAH19的过表达密切相关。β-榄香烯和吉非替尼的协同给药显著减弱耐药细胞的增殖能力，加速凋亡过程，并抑制肺癌的体内增殖。值得注意的是,β-榄香烯极大地减少了lncRNAH19的表达，并降低了抗性细胞中的自噬活性，从而增强他们对吉非替尼的反应性。此外，β-榄香烯破坏了Rab7促进的EGFR降解途径，促进其重新定位到质膜。β-榄香烯是一种有前途的辅助治疗方法，用于规避非小细胞肺癌吉非替尼耐药，可能通过调节lncRNAH19介导的自噬。Rab7参与这一动态揭示了对肺癌耐药机制的新见解，为未来的治疗创新铺平道路。
