Muscadine grape skin extract can antagonize Snail-cathepsin L-mediated invasion, migration and osteoclastogenesis in prostate and breast cancer cells.

Carcinogenesis. 2015 Sep;36(9):1019-27. doi: 10.1093/carcin/bgv084. Epub 2015 Jun 10.

Burton LJ¹, Smith BA¹, Smith BN¹, Loyd Q¹, Nagappan P¹, McKeithen D¹, Wilder CL², Platt MO², Hudson T³, Odero-Marah VA⁴.

Author information

• ¹Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA and Department of Medicine, Howard University, Washington, DC 20060, USA.
• ²Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA and.
• ³Department of Medicine, Howard University, Washington, DC 20060, USA.
• ⁴Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA and Department of Medicine, Howard University, Washington, DC 20060, USA vodero_marah@cau.edu.

Abstract

To develop new and effective chemopreventive agents against bone metastasis, we assessed the effects of muscadine grape skin extract (MSKE), whose main bioactive component is anthocyanin, on bone turnover, using prostate and breast cancer cell models overexpressing Snail transcription factor. MSKE has been shown previously to promote apoptosis in prostate cancer cells without affecting normal prostate epithelial cells. Snail is overexpressed in prostate and breast cancer, and is associated with increased invasion, migration and bone turnover/osteoclastogenesis. Cathepsin L (CatL) is a cysteine cathepsin protease that is overexpressed in cancer and involved in bone turnover. Snail overexpression in prostate (LNCaP, ARCaP-E) and breast (MCF-7) cancer cells led to increased CatL expression/activity and phosphorylated STAT-3 (pSTAT-3), compared to Neo vector controls, while the reverse was observed in C4-2 (the aggressive subline of LNCaP) cells with Snail knockdown. Moreover, CatL expression was higher in prostate and breast tumor tissue compared to normal tissue. MSKE decreased Snail and pSTAT3 expression, and abrogated Snail-mediated CatL activity, migration and invasion. Additionally, Snail overexpression promoted osteoclastogenesis, which was significantly inhibited by the MSKE as effectively as Z-FY-CHO, a CatL-specific inhibitor, or osteoprotegerin, a receptor activator of nuclear factor kappa B ligand (RANKL) antagonist. Overall, these novel findings suggest that Snail regulation of CatL may occur via STAT-3 signaling and can be antagonized by MSKE, leading to decreased cell invasion, migration and bone turnover. Therefore, inhibition using a natural product such as MSKE could potentially be a promising bioactive compound for bone metastatic cancer.
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