The potential role of AhR/NR4A1 in androgen-dependent prostate cancer: focus on TCDD-induced ferroptosis

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Prostate cancer (PCa) presents diverse molecular alterations.
• The aryl hydrocarbon receptor (AhR) plays varied roles in PCa.
• Targeting ferroptosis is a promising therapeutic strategy for PCa, but AhR's role is not well understood.

Purpose of the Study:

• To investigate the influence of AhR activation on lipid peroxidation and ferroptosis in PCa.
• To elucidate the molecular mechanisms underlying AhR's effect on ferroptosis.

Main Methods:

• Treated PCa cells and in vivo models with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AhR ligand.
• Assessed cell viability, mitochondrial morphology, lipid peroxidation markers (MDA, 4-HNE), and the GSH/GSSG ratio.
• Utilized AhR knockdown and NR4A1 overexpression to explore mechanistic pathways.
• Measured expression levels of CYP1A1, NR4A1, and SCD1.

Main Results:

• TCDD activated AhR, increasing CYP1A1 expression and reducing cell viability.
• TCDD induced ferroptosis hallmarks: mitochondrial shrinkage, decreased GSH/GSSG ratio, and elevated lipid peroxidation.
• AhR knockdown reversed TCDD-induced ferroptosis.
• TCDD suppressed NR4A1 expression, subsequently downregulating its target SCD1.
• NR4A1 overexpression counteracted TCDD's effects.
• In vivo studies confirmed AhR activation, NR4A1/SCD1 downregulation, and increased ferroptosis markers.

Conclusions:

• TCDD promotes ferroptosis in androgen-dependent PCa through AhR activation.
• The mechanism involves the inhibition of the NR4A1/SCD1 axis.
• These findings highlight the NR4A1/SCD1 pathway as a potential therapeutic target in PCa.