A novel inhibitor isoimperatorin targeting YWHAZ suppresses human lung adenocarcinoma activity by activating autophagy

Background: Precise targeted therapy for lung cancer is a key strategy that benefits patients. Existing research indicates that Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) plays a role as an oncogene in the occurrence and development of lung cancer. However, there are currently few targeted inhibitors developed against YWHAZ. This study investigated a novel small-molecule drug, isoimperatorin, targeted inhibit YWHAZ and further indicated the anti-tumor effects in vitro and in vivo . We intend to provide a promising therapeutic strategy for lung adenocarcinoma with high YWHAZ gene expression. Methods: The Cancer Genome Atlas (TCGA) database was used to assess YWHAZ expression in Non-small cell lung cancer and normal lung tissues. We detected YWHAZ expression in different types of lung cancer tissue. A high-throughput dual-luciferase reporter system was used to screen YWHAZ-targeting inhibitors. The fuction experiment of tumor cell and mice xenografts were used to investigate the roles of YWHAZ and the antitumor activity of the targeted inhibitors in lung adenocarcinoma in vitro and in vivo . Western blotting was conducted to preliminarily explore potential mechanisms. Results: We revealed high expression of YWHAZ in clinical lung cancer tissues, which was associated with poor prognosis. Knockdown of YWHAZ in lung adenocarcinoma cells impaired the malignant functions, and inhibited the tumor growth in mice xenograft. Isoimperatorin exhibited significant inhibitory effects on the viability of lung adenocarcinoma cells, but its effect on the cells with YWHAZ knockdown was not significant. Treatment with isoimperatorin in lung adenocarcinoma cells inhibited the malignant functions and suppressed tumor growth in mice xenografts. More importantly, we found PI3K/AKT signaling pathway is suppressed after YWHAZ was targeting inhibited by isoimperatorin, while autophagy-related proteins and apoptosis-related proteins were activated. Conclusion: Our study indicates that YWHAZ plays an oncogenic role as a core target molecule in lung adenocarcinoma. As a novelly targeted inhibitor, isoimperatorin effectively inhibited YWHAZ gene with potent antitumor activities in lung adenocarcinoma. The underlying mechanism may involve inhibition of PI3K/AKT signaling pathway, then activating cell autophagy, and subsequently promoting cell apoptosis.