Abstract A010: Gloriosine induces cell cycle arrest by autophagic cell death through negative regulation of YAP transcriptional activity in non-small cell lung cancer. Gloriosine is a potent alkaloid derivative having potent anti cancer activity

Abstract

Abstract Autophagy plays a dual role in the development and advancement of various tumor. YAP, a component of the Hippo pathway, is known to be associated with autophagy. This study aims to explore the relationship between YAP and autophagy with respect to cell death pathway in lung cancer. Non-small cell lung cancer (NSCLC) accounts for most of the cancer death among all types of lung cancer. Here, we explored antiproliferative and antimigratory effect of compound gloriosine on A549 cells through Autophagy/Hippo signalling pathway. In the present study, we demonstrated that gloriosine inhibits cell viability of A549 cell lines (at 100nM concentration of 24 hours of treatment) in vitro by inducing autophagy with very low toxicity to normal breast cells MCF10A (>1000nM). At 100nM concentration gloriosine led to G2/M cell cycle arrest after an hour of treatment in A549 cell lines. Furthermore, it affects (at 25nM) Hippo signalling through retention of YAP protein into cytoplasm and inhibiting YAP localization into nucleus, suppressing the expression of downstream target gene. Inhibition of YAP localization supresses AKT/mTOR pathway which ultimately leads to activation of autophagy dependent cell death. Spheroid formation assay reveals gloriosine treatment can inhibits tumor relapse and reduce the size of the spheroid of A549 cells in a dose dependent manner. This molecule also inhibits lung cancer tumor growth in nude mice at 27% and 64% with dose of 1mg/kg and 5mg/kg body weight respectively. These current results suggest that gloriosine has the potential to serve as a new anticancer drug candidate. Citation Format: Biswajit Dey, Bharat Goel, Essha Chatterjee, Hoshiyar Singh, Shreyans Jain, Santosh Kumar Guru. Gloriosine induces cell cycle arrest by autophagic cell death through negative regulation of YAP transcriptional activity in non-small cell lung cancer. Gloriosine is a potent alkaloid derivative having potent anti cancer activity [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A010.