Gilteritinib suppresses prostate cancer cell proliferation and migration and induces ER stress-mediated non-autophagic cytoplasmic vacuolization cell death.

Abstract

Prostate cancer (PCa) is a leading malignancy among men and lacks effective treatment, particularly for metastatic stages. Metastasis contributes significantly to cancer morbidity and mortality. Gilteritinib showed anticancer activity against lung and colorectal cancer but has not been thoroughly investigated for its potential in PCa therapy. This study evaluated the anticancer effects of gilteritinib on PCa cell lines (PC3 and DU145) by assessing cytotoxicity, cell proliferation, colony formation, and migration. Mechanistic studies were conducted to determine its impact on the cell cycle, epithelial-to-mesenchymal transition (EMT), and Wnt/β-catenin signaling. Additionally, the mode of cell death was explored, focusing on endoplasmic reticulum (ER) stress and protein ubiquitination. Gilteritinib exhibited dose-dependent cytotoxicity and inhibited PCa cell proliferation, colony formation, and migration. It induced G1 phase cell cycle arrest by downregulating CDK2, CDK4, and cyclin E1. EMT modulation was observed through the suppression of vimentin, N-cadherin, and Twist, along with increased E-cadherin expression. This EMT inhibition correlated with the downregulation of Wnt/β-catenin signaling components. Notably, gilteritinib triggered a non-apoptotic, non-autophagic cell death characterized by cytoplasmic vacuolation, ER stress, and protein ubiquitination, requiring new protein synthesis. This effect was mediated through the activation of the unfolded protein response (UPR) via the PERK pathway. Gilteritinib demonstrates significant anticancer potential in PCa by inducing cell cycle arrest, inhibiting EMT, suppressing Wnt/β-catenin signaling, and triggering a unique mode of cell death via ER stress. These findings highlight gilteritinib as a promising therapeutic candidate for PCa treatment.