N6-methyladenosine (m6A) modification can alter gene expression by regulating RNA splicing, stability, translocation, and translation. Emerging evidence shows that m6A modification plays an important role in cancer development and progression, including cell proliferation, migration and invasion, cell apoptosis, autophagy, and drug resistance. Until now, the role of m6A modification mediated autophagy in cancer drug resistance is still unclear. In this study, we found that m6A methyltransferase METTL3-mediated autophagy played an important role in reversing gefitinib resistance by β-elemene in non-small cell lung cancer (NSCLC) cells. Mechanistically, in vitro and in vivo studies indicated that β-elemene could reverse gefitinib resistance in NSCLC cells by inhibiting cell autophagy process in a manner of chloroquine. β-elemene inhibited the autophagy flux by preventing autophagic lysosome acidification, resulting in increasing expression of SQSTM1 and LC3B-II. Moreover, both β-elemene and gefitinib decreased the level of m6A methylation of gefitinib resistance cells. METTL3 was higher expressed in lung adenocarcinoma tissues than that of paired normal tissues, and was involved in the gefitinib resistance of NSCLC cells. Furthermore, METTL3 positively regulated autophagy by increasing the critical genes of autophagy pathway such as ATG5 and ATG7. In conclusion, our study unveiled the mechanism of METTL3-mediated autophagy in reversing gefitinib resistance of NSCLC cells by β-elemene, which shed light on providing potential molecular-therapy target and clinical-treatment method in NSCLC patients with gefitinib resistance.

译文

:N6-甲基腺苷(m6A)修饰可通过调节RNA剪接,稳定性,易位和翻译来改变基因表达。新兴证据表明,m6A修饰在癌症的发展和进程中起着重要作用,包括细胞增殖,迁移和侵袭,细胞凋亡,自噬和耐药性。到目前为止,尚不清楚m6A修饰介导的自噬在癌症耐药中的作用。在这项研究中,我们发现m6A甲基转移酶METTL3介导的自噬在非小细胞肺癌(NSCLC)细胞中逆转β-榄香烯对吉非替尼的耐药性中起重要作用。从机制上,体外和体内研究表明,β-榄香烯可以通过抑制细胞自噬过程以氯喹的方式逆转NSCLC细胞中的吉非替尼耐药性。 β-榄香烯通过阻止自噬溶酶体酸化来抑制自噬通量,从而导致SQSTM1和LC3B-II的表达增加。此外,β-榄香烯和吉非替尼均降低了吉非替尼耐药细胞的m6A甲基化水平。 METTL3在肺腺癌组织中的表达高于配对的正常组织,并参与了NSCLC细胞的吉非替尼耐药性。此外,METTL3通过增加自噬途径的关键基因如ATG5和ATG7来正向调节自噬。综上,我们的研究揭示了METTL3介导的自噬通过β-榄香烯逆转NSCLC细胞对吉非替尼耐药的机制,为为吉非替尼耐药的NSCLC患者提供了潜在的分子治疗靶点和临床治疗方法。

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