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  3. The mechanism of m6A methyltransferase METTL3-mediated autophagy in reversing gefitinib resistance in NSCLC cells by β-elemene

The mechanism of m6A methyltransferase METTL3-mediated autophagy in reversing gefitinib resistance in NSCLC cells by β-elemene

  • Cell Death Dis. 2020 Nov 11;11(11):969. doi: 10.1038/s41419-020-03148-8.
Shuiping Liu 1 2,  Qiujie Li 1 2,  Guohua Li 1 2,  Qin Zhang 1 2,  Lvjia Zhuo 1 2,  Xuemeng Han 1 2,  Mingming Zhang 1 2,  Xiaying Chen 1 2,  Ting Pan 1 2,  Lili Yan 1 2,  Ting Jin 1 2,  Jianjun Wang 3,  Qun Lv 4,  Xinbing Sui 5 6,  Tian Xie 7 8
Affiliations

Affiliations

  • 1 College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
  • 2 Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
  • 3 Department of Respiratory medicine, the Affiliated Hospital of Hangzhou Normal University, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, 310015, China.
  • 4 Department of Respiratory medicine, the Affiliated Hospital of Hangzhou Normal University, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, 310015, China. hzlvqun@126.com.
  • 5 College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China. hzzju@zju.edu.cn.
  • 6 Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China. hzzju@zju.edu.cn.
  • 7 College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China. xbs@hznu.edu.cn.
  • 8 Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China. xbs@hznu.edu.cn.
PMID: 33177491 DOI: 10.1038/s41419-020-03148-8
Abstract

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.

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