Gut Bacterial Metabolite Urolithin A Decreases Actin Polymerization and Migration in Cancer Cells

• Published in: Molecular nutrition & food research Vol. 64; no. 7; pp. e1900390 - n/a
• Main Authors: Alauddin, Md, Okumura, Toshiyuki, Rajaxavier, Janet, Khozooei, Shayan, Pöschel, Simone, Takeda, Satoru, Singh, Yogesh, Brucker, Sara Y, Wallwiener, Diethelm, Koch, André, Salker, Madhuri S
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.04.2020
• Subjects: Actin; actin polymerization; Botulinum toxin; Cancer; carcinoma cells; Cell growth; Cell migration; Cell proliferation; Cytoskeleton; Depolymerization; Diet; Ellagic acid; Flow cytometry; Fruits; GTP-binding protein; Immunoblotting; Immunofluorescence; Kinases; Metabolites; Nuts; PAK1; Polymerization; Pomegranates; Rac1; Rac1 protein; siRNA; Substrates; Toxins; Transcription; Western blotting; Wound healing; actin polymerization; carcinoma cells; PAK1; Rac1
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201900390

Scope Urolithin A (UA) is a gut‐derived bacterial metabolite from ellagic acid found in pomegranates, berries, and nuts can downregulate cell proliferation and migration. Cell proliferation and cell motility require actin reorganization, which is under control of ras‐related C3 botulinum toxin substrate 1 (Rac1) and p21 protein‐activated kinase 1 (PAK1). The present study explores whether UA can modify actin cytoskeleton in cancer cells. Methods The effect of UA on globular over filamentous actin ratio is determined utilizing Western blotting, immunofluorescence, and flow cytometry. Rac1 and PAK1 levels are measured by quantitative RT‐PCR and immunoblotting. As a result, a 24 h treatment with UA (20 µm) significantly decreased Rac1 and PAK1 transcript levels and activity, depolymerized actin and wound healing. The effect of UA on actin polymerization is mimicked by pharmacological inhibition of Rac1 and PAK1. The effect is also mirrored by knock down using siRNA. Conclusion UA leads to disruption of Rac1 and Pak1 activity with subsequent actin depolymerization and migration. Thus, use of dietary UA in cancer prevention or as adjuvant therapy is promising. Ellagic acid, from red berries or fruits, is metabolized in the intestine to produce urolithins. It is shown specifically that Urolithin A reduces the Rac1 and PAK1 activity that leads to a decrease in actin polymerization, thus leading to reduced cell migration in human endometrial carcinoma cells.