YAP inhibition by gloriosine unlocks autophagic cell death as an anticancer strategy in lung malignancies.

Historically, lung cancer has been considered the leading cause of cancer-related death worldwide. Though some of the chemotherapeutic agents show promising outcomes in the ongoing battle against cancer, the overall survival rate for advanced-stage disease remains poor due to drug resistance, toxicity, and limited efficacy. Therefore, new chemotherapeutic agents are required to enhance efficacy, reduce side effects, and combat drug resistance. In the present study, we isolated a compound, gloriosine, and investigated its anticancer potential against different cancer cells, with a special focus on A549 lung adenocarcinoma cells. Treatment with gloriosine resulted in a significant reduction in cell viability in a dose- and time-dependent manner and reduced tumor size in the tumor xenograft model. Interestingly, gloriosine exhibited minimal cytotoxicity on normal cells, indicating its selective activity on cancer cells. Mechanistically, gloriosine induced G2/M cell cycle arrest in A549 cells within an hour of treatment and was found to affect the Hippo signaling pathway, leading to the retention and phosphorylation of the Yes-associated protein (YAP) in the cytoplasm, thereby inhibiting the activation of downstream target genes. This, in turn, led to the suppression of the AKT/mTOR pathway and the activation of autophagy-dependent cell death. These findings suggest that gloriosine could be a promising candidate for the development of new lung cancer therapies.