Auranofin Suppresses Cancer Cell Invasion by Inhibiting Heparanase-1 Expression via the aPKC-NF-κB Pathway

Area of Science:

• Oncology
• Biochemistry
• Drug Discovery

Background:

• Heparanase 1 (HPSE1) promotes cancer progression through enzymatic and non-enzymatic functions, but lacks FDA-approved inhibitors.
• Existing therapeutic strategies targeting HPSE1's enzymatic activity are limited by its multifaceted roles in cancer.

Purpose of the Study:

• To identify novel inhibitors of HPSE1 expression.
• To investigate the therapeutic potential of repurposing existing drugs for cancer treatment targeting HPSE1.

Main Methods:

• High-throughput screening identified auranofin (AUF) as an inhibitor of HPSE1 promoter activity.
• Investigated the role of the atypical protein kinase C (aPKC)-NF-κB signaling axis in regulating HPSE1 expression.
• Assessed the effect of AUF on HPSE1 expression and cancer cell invasion using Transwell migration assays.

Main Results:

• Auranofin (AUF) significantly reduced HPSE1 expression by inhibiting the aPKC-NF-κB signaling pathway.
• AUF treatment suppressed the invasive capacity of MDA-MB-231 breast cancer cells.
• Cancer cell invasion depends on mesenchymal features and coordinated induction of HPSE1 and GAGs, not solely HS degradation.

Conclusions:

• Auranofin (AUF) is a potent inhibitor of HPSE1 expression, offering a potential therapeutic strategy for various cancers.
• Targeting HPSE1 expression with AUF can inhibit both enzymatic and non-enzymatic functions, limiting cancer progression, metastasis, and angiogenesis.
• Repurposing auranofin (AUF) for cancer treatment warrants further investigation.