Androgen Receptor-Induced Lactoferrin Accelerates Prostate Tumorigenesis Through Modulating Ferroptosis

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Lactoferrin (LF) is highly expressed in the prostate, suggesting a key physiological role.
• While LF is tumor-suppressive in other cancers, its function in prostate cancer is unclear.

Purpose of the Study:

• To investigate the role of lactoferrin in prostate cancer.
• To elucidate the mechanism of lactoferrin's function in prostate cancer through the androgen receptor (AR)-LF-ferroptosis axis.

Main Methods:

• Utilized Lf knockout TRAMP mouse models, proteomics, TCGA-PARD data, and single-cell RNA-seq.
• Investigated AR binding to the LF promoter and its effect on ferritin expression and ferroptosis.
• Conducted preclinical studies using LF knockdown, ferroptosis inducers (IKE), and AR inhibitors (enzalutamide) in xenograft models.

Main Results:

• AR directly upregulates LF expression, which suppresses ferroptosis by increasing ferritin and inhibiting p53-ALOX12.
• LF deficiency delayed tumor progression and increased ferroptosis in TRAMP mice; iron supplementation accelerated cancer, an effect reversed by LF knockout.
• Lactoferrin protects prostate cancer cells from iron-induced ferroptosis by maintaining iron-redox homeostasis.

Conclusions:

• Lactoferrin acts as an AR-regulated suppressor of ferroptosis in prostate cancer.
• LF regulates prostate cancer's dependence on iron metabolism.
• LF is a potential therapeutic target for exploiting prostate cancer's iron-metabolic vulnerability.