title: Muscadine grape skin extract can antagonize Snail-cathepsin L-mediated invasion, migration and osteoclastogenesis in prostate and breast cancer cells.
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.
authors.affiliation: Department 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.
authors.forename: Liza J
authors.initials: LJ
authors.lastname: Burton
authors.affiliation: Department 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.
authors.forename: Basil A
authors.initials: BA
authors.lastname: Smith
authors.affiliation: Department 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.
authors.forename: Bethany N
authors.initials: BN
authors.lastname: Smith
authors.affiliation: Department 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.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Loyd
authors.affiliation: Department 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.
authors.forename: Peri
authors.initials: P
authors.lastname: Nagappan
authors.affiliation: Department 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.
authors.forename: Danielle
authors.initials: D
authors.lastname: McKeithen
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA and.
authors.forename: Catera L
authors.initials: CL
authors.lastname: Wilder
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30322, USA and.
authors.forename: Manu O
authors.initials: MO
authors.lastname: Platt
authors.affiliation: Department of Medicine, Howard University, Washington, DC 20060, USA.
authors.forename: Tamaro
authors.initials: T
authors.lastname: Hudson
authors.affiliation: Department 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.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Odero-Marah
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology*; D056668:Cathepsin L / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018890:Chemoprevention / Q000379:methods; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010010:Osteoclasts / Q000166:cytology; D010012:Osteogenesis / Q000187:drug effects; D053244:Osteoprotegerin / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000473:pathology*; D053245:RANK Ligand / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D027843:Vitis / Q000737:chemistry*
chemical_list: D016588:Anticarcinogenic Agents; D053244:Osteoprotegerin; D010936:Plant Extracts; D053245:RANK Ligand; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071250:Snail Family Transcription Factors; C505688:TNFSF11 protein, human; D014157:Transcription Factors; C534281:CTSL protein, human; D056668:Cathepsin L