Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P.R. China.
Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China.
Oncol Rep. 2021 Jul;46(1). doi: 10.3892/or.2021.8100. Epub 2021 Jun 3.
Multidrug resistance (MDR) is one of the major reasons for the clinical failure of cancer chemotherapy. Autophagy activation serves a crucial role in MDR. However, the specific molecular mechanism linking autophagy with MDR remains unknown. The results of the present study demonstrated that autophagy was inhibited and microRNA (miR)‑199a‑5p levels were upregulated in MDR model lung cancer cells (A549/T and H1299/T) compared with those in the parental cell lines. Paclitaxel (PTX) treatment increased the expression levels of miR‑199a‑5p in parental lung cancer cells compared with those in PTX‑untreated cells, and these expression levels were negatively correlated with PTX sensitivity of the cells. miR‑199a‑5p knockdown in A549/T cells induced autophagy and resensitized cells to multiple chemotherapeutic drugs including PTX, taxotere, topotecan, SN38, oxaliplatin and vinorelbine. By contrast, miR‑199a‑5p overexpression in A549 cells suppressed autophagy and desensitized cells to these chemotherapeutic drugs. Mechanistically, the results of the present study demonstrated that miR‑199a‑5p blocked autophagy by activating the PI3K/Akt/mTOR signaling pathway and inhibiting the protein expression of autophagy‑related 5. Furthermore, p62 protein was identified as a direct target of miR‑199a‑5p; miR‑199a‑5p bound to p62 mRNA to decrease its mRNA and protein expression levels. In conclusion, the results of the present study suggested that miR‑199a‑5p may contribute to MDR development in lung cancer cells by inhibiting autophagy and targeting p62. The regulatory effect of miR‑199a‑5p on autophagy may provide novel insights for future multidrug‑resistant lung cancer chemotherapy.
多药耐药（MDR）是癌症化疗临床失败的主要原因之一。自噬激活在 MDR 中起着至关重要的作用。然而，将自噬与 MDR 联系起来的具体分子机制尚不清楚。本研究结果表明，与亲本细胞系相比，耐药模型肺癌细胞（A549/T 和 H1299/T）中自噬受到抑制，microRNA（miR）-199a-5p 水平上调。与未用紫杉醇（PTX）处理的细胞相比，PTX 处理增加了亲本肺癌细胞中 miR-199a-5p 的表达水平，并且这些表达水平与细胞对 PTX 的敏感性呈负相关。A549/T 细胞中 miR-199a-5p 的敲低诱导自噬，并使细胞对包括 PTX、多西他赛、拓扑替康、SN38、奥沙利铂和长春瑞滨在内的多种化疗药物重新敏感。相比之下，A549 细胞中 miR-199a-5p 的过表达抑制了自噬，并使细胞对这些化疗药物脱敏。从机制上讲，本研究结果表明，miR-199a-5p 通过激活 PI3K/Akt/mTOR 信号通路和抑制自噬相关蛋白 5 的蛋白表达来阻断自噬。此外，p62 蛋白被鉴定为 miR-199a-5p 的直接靶标；miR-199a-5p 与 p62 mRNA 结合，降低其 mRNA 和蛋白表达水平。总之，本研究结果表明，miR-199a-5p 通过抑制自噬和靶向 p62 可能有助于肺癌细胞的 MDR 发展。miR-199a-5p 对自噬的调节作用可能为未来多药耐药性肺癌化疗提供新的见解。
