TAZ inhibition restores sensitivity of cisplatin via AKT/mTOR signaling in lung adenocarcinoma.

Abstract

The cisplatin-based doublet remains the foundation of treatment for the majority of patients with advanced non-small cell lung cancer (NSCLC), however, many patients exhibit acquired drug resistance. Transcriptional co-activator with PDZ binding motif (TAZ) is an oncogene in lung cancer, important for lung tumorigenesis and metastasis. Recently, it was revealed that TAZ upregulation confers resistance against a diverse range of cytotoxic agents. The present study aimed to investigate whether TAZ is involved in cisplatin sensitivity in lung adenocarcinoma. In the present study, we investigated TAZ expression in lung adenocarcinoma tissues and cell lines with western blot and RT-PCR analyses. By knocking down TAZ using short hairpin RNAs in cisplatin-resistant A549 and H460 cells, cell proliferation and apoptosis were assessed by BrdUrd labeling and flow cytometric analysis, respectively. The IC50 value of cisplatin was also assessed with CCK-8 assays. The western blotting for AKT, p-AKT, S6K and p-S6K were performed in cells with TAZ knockdown or overexpression. When the AKT/mTOR pathway was blocked in A549 and H460 with TAZ overexpression, cisplatin sensitivity was assessed by IC50 value. High expression of TAZ was found in lung adenocarcinoma tissues and cell lines, which were associated with cisplatin resistance. Knockdown of TAZ using shRNAs confered decreasing proliferation, increasing apoptosis and enhanced cisplatin sensitivity in cisplatin‑resistant cells. Additionally, TAZ knockdown decreased the AKT/mTOR pathway expression. Overexpression of TAZ increased p-AKT and p-S6K, which was inhibited by siAKT. Furthermore, we found that the inhibition of the AKT/mTOR pathway rescued the cells from cisplatin resistance caused by TAZ overexpression. Our data revealed that TAZ inhibition restores sensitivity of cisplatin in lung adenocarcinoma, which was, at least in part, AKT/mTOR signaling pathway-dependent. TAZ may be a potent therapeutic target for NSCLC in combination with conventional chemotherapy.