Autophagy inhibition and microRNA-199a-5p upregulation in paclitaxel-resistant A549/T lung cancer cells

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.