MiTF is Associated with Chemoresistance to Cisplatin in A549 Lung Cancer Cells via Modulating Lysosomal Biogenesis and Autophagy

BACKGROUND: Non-small cell lung carcinoma (NSCLC) is often fatal; advanced NSCLC has a 5-year survival rate less than 20%. Platinum-based chemotherapy, in particular, cis-diamminedichloroplatinum (II) (cisplatin or DDP), is employed for the treatment of NSCLC; however, the drug resistance occurs frequently. Autophagy is defined as the process of intracellular degradation of cytoplasmic materials in the lysosome; however, the correlation between autophagy and drug resistance remains controversial. Herein, we investigated the correlation between autophagy and cisplatin resistance and also explored the underlying mechanisms. METHODS AND RESULTS: We demonstrated that DDP-resistant NSCLC A549 (A549/DDP) cells had higher autophagy activity in comparison with its parental A549 cells; DDP treatment induced a time- and dose-dependent decrease of autophagy. Intriguingly, inhibition of autophagy with pharmacological drugs or knockdown of ATG5 or Beclin-1 aggravated cell death induced by DDP treatment, indicating that autophagy played protective roles during DDP treatment. Further mechanistic investigation revealed that DDP treatment could decrease the mRNA expression level of key autophagy-related genes, such as ATG5, Beclin-1, and ATG7, suggesting DDP repressed autophagy at the transcriptional level. The MiTF/TFE family (including TFEB, TFE3, TFEC, and MiTF) were involved in nutrient sensing and organelle biogenesis, and specifically, the lysosomal biogenesis. We found that only MiTF was dramatically decreased upon DDP treatment, and also a profound decrease of lysosomal markers, LAMP-1 or LAMP-2, suggesting that MiTF was involved in the modulation of lysosomal biogenesis and, consequently, the autophagy. Moreover, the knockdown of MiTF resulted in more severe cell death in A549/DDP cells, indicting the substantial correlation between MiTF and cisplatin chemoresistance. CONCLUSION: Our study provides novel insights into the association between MiTF and DDP chemoresistance in NSCLC cells, and suggests targeting MiTF and/or autophagy might be a potential strategy for the reversal of DDP chemoresistance for NSCLC treatment.