Disruption of Protein Homeostasis by Targeting Autophagosome Formation: A Novel Anticancer Strategy Inducing Cell Death

Abstract

Dysregulation of intracellular protein homeostasis is closely associated with various major diseases, particularly malignant tumors. Such disruptions may arise from altered protein synthesis, protein misfolding, and dysfunction of degradation pathways such as the ubiquitin–proteasome system (UPS) and the autophagy–lysosome system. Cancer cells, characterized by rapid proliferation, require extensive protein synthesis during tumorigenesis and progression, making proteinhomeostasis- related mechanisms attractive anticancer targets. The complete autophagic process includes substrate accumulation, autophagosome formation, and subsequent degradation of cellular components. Although autophagy represents a potential therapeutic target in cancer, its dual role in promoting either cell survival or cell death complicates its clinical utility. In this study, we demonstrate that targeting autophagosome formation can block autophagic flux and induce incomplete autophagic cell death. Mechanisms that impair autophagosome formation include inhibition of nucleation by ULK1 and ATG13, disruption of lipid transport, interference with membrane extension, and defects in ESCRT-mediated closure. Each of these pathways obstructs autophagosome biogenesis, leading to substrate accumulation and ultimately triggering cell death.