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.
Keywords: autophagy; lung cancer cells; microRNA‑199a‑5p; multidrug resistance; p62 protein.