NOX2-Mediated TFEB Activation and Vacuolization Regulate Lysosome-Associated Cell Death Induced by Gypenoside L, a...

Area of Science:

• Oncology
• Cell Biology
• Pharmacology

Background:

• Chemoresistance in tumor cells is often linked to reduced apoptosis and increased autophagy.
• Novel therapeutic strategies are needed to induce non-apoptotic and non-autophagic cell death, such as lysosome-associated cell death.
• Gypenoside L (Gyp-L), a saponin from Gynostemma pentaphyllum, has shown potential in inducing nonapoptotic cell death in esophageal cancer cells.

Purpose of the Study:

• To elucidate the mechanisms underlying Gyp-L-induced lysosome-associated cell death.
• To investigate the roles of vacuolization, lysosomal function, and NADPH oxidase NOX2 in Gyp-L's cytotoxic effects.
• To explore the potential of Gyp-L as an alternative agent to overcome cancer drug resistance.

Main Methods:

• Extraction and characterization of Gyp-L from Gynostemma pentaphyllum.
• Induction of cell death in esophageal cancer cells treated with Gyp-L.
• Analysis of vacuole formation, lysosomal pH, and TFEB activation.
• Investigation of NOX2 involvement and lipid raft-dependent endocytosis pathways.

Main Results:

• Gyp-L induces nonapoptotic cell death associated with lysosome swelling and vacuolization.
• Vacuoles are enlarged, alkalized, and derived from lipid raft-dependent endocytosis.
• NADPH oxidase NOX2 activation promotes vacuolization and mTORC1-independent TFEB-mediated lysosome biogenesis.
• Increasing lysosomal pH potentiates Gyp-L-induced cancer cell death.

Conclusions:

• NOX2 and TFEB play critical roles in Gyp-L-induced lysosome-associated cell death.
• Lysosome biogenesis, mediated by NOX2-TFEB, may be a protective mechanism against cancer drug resistance.
• Gyp-L represents a promising natural compound for overcoming drug resistance by inducing lysosome-associated cell death.