Transglutaminase 2 expression levels regulate sensitivity to cystamine plus TRAIL-mediated apoptosis

Area of Science:

• Biochemistry
• Cell Biology
• Oncology

Background:

• Transglutaminase 2 (TG2) plays a role in cellular processes.
• Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) is a key mediator of apoptosis.
• Cancer cells often exhibit altered TG2 expression levels.

Purpose of the Study:

• To investigate the effect of cystamine, a TG2 inhibitor, on TRAIL-mediated apoptosis.
• To determine the role of TG2 in cystamine and TRAIL synergy.
• To explore the potential of cystamine as a sensitizer for TRAIL-based cancer therapy.

Main Methods:

• Utilized Caki cells and normal human mesangial cells.
• Administered cystamine and TRAIL, alone and in combination.
• Assessed apoptosis induction and c-FLIP levels.
• Employed pancaspase inhibitor z-VAD and TG2 siRNA for mechanistic studies.

Main Results:

• Cystamine potentiated TRAIL-induced apoptosis in Caki cells, but not normal mesangial cells.
• Cystamine plus TRAIL led to c-FLIP down-regulation, reversible by z-VAD.
• Overexpression of c-FLIP reduced cystamine plus TRAIL-induced apoptosis.
• Cells with higher TG2 levels showed increased sensitivity, which was abrogated by TG2 knockdown.

Conclusions:

• TG2 levels modulate the sensitivity of cancer cells to cystamine and TRAIL.
• Cystamine acts as a sensitizer, enhancing TRAIL-induced apoptosis.
• Cystamine may be a promising therapeutic agent for cancers with high TG2 expression.