Glaucocalyxin A Induces Cytotoxicity in Renal Cancer Cells via ROS-Mediated Autophagy by Direct Targeting of...

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Glaucocalyxin A (GLA), a diterpenoid from Rabdosia japonica, shows antitumor potential.
• The precise molecular mechanisms of GLA in renal cell carcinoma (RCC) are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying GLA's cytotoxicity in RCC.
• To identify the direct molecular targets of GLA in RCC cells.

Main Methods:

• Utilized activity-based protein profiling (ABPP) and proteomic analysis to identify GLA targets.
• Investigated the roles of reactive oxygen species (ROS) and autophagy in GLA-induced cytotoxicity.
• Performed functional validation of identified targets, including PRDX1/2, in RCC cells.

Main Results:

• GLA induces cytotoxicity in RCC cells via overaccumulation of reactive oxygen species (ROS).
• ROS surge activates autophagy, which acts as a crucial effector in GLA-induced cell death.
• Peroxiredoxins PRDX1 and PRDX2 were identified as direct covalent targets of GLA.
• Overexpression of PRDX1/2 confers resistance to GLA-induced apoptosis, highlighting their role in redox sensing.

Conclusions:

• GLA triggers a cascade involving ROS accumulation, autophagy activation, and apoptosis in RCC cells.
• PRDX1/2 are critical targets and redox sensors that mediate GLA's cytotoxic effects.
• GLA represents a promising therapeutic scaffold for developing novel treatments for renal cell carcinoma.